MXPA00003055A - Apolipoprotein a-i agonists and their use to treat dyslipidemic disorders - Google Patents

Abstract

The present invention provides peptides and peptide analogues that mimic the structural and pharmacological properties of human ApoA-I. The peptides and peptide analogues are useful to treat a variety of disorders associated with dyslipidemia.

Description

AGENTS OF APOLIPOPROTEÍ AI AND ITS USE TO TREAT DISLIPIDEMIC DISEASES c »1. INTRODUCTION The invention relates to the compositions of apolipoprotein A-1 agonists (ApoA-I) to treat abnormalities associated with dyslipoproteinemia, including hypercholesterolemia, cardiovascular disease , atherosclerosis, restenosis and other abnormalities such as shock septic. 2. BACKGROUND OF THE INVENTION Circulating cholesterol is carried by plasma lipoproteins - particles of the composition complex lipid and protein that transports lipids in the blood. Low density lipoproteins (LDL), and high density lipoproteins (HDL) are the main carriers of cholesterol. It is considered that LDL are responsible for the supply of cholesterol from the liver (where it is synthesized or obtained from dietary sources) to extra hepatic tissues in the body. The term "reverse cholesterol transport" describes a transport of cholesterol from extrahepatic tissues to the liver where it is catabolized and eliminated. Is considered that the HDL particles of the plasma have an important activity in the reverse transport process, acting as tissue cholesterol scavengers. The evidence that links the high concentration of serum cholesterol with coronary heart disease is outstanding. For example, atherosclerosis is a slowly progressive disease characterized by the accumulation of cholesterol center of the arterial wall. There is precise evidence that supports the concept that the lipids deposited in atherosclerotic lesions come from mainly of the plasma LDL; thus, LDL is now commonly known as "bad" cholesterol. On the contrary, serum HDL concentrations correlate inversely with coronary heart disease, in fact, high serum HDL concentrations are considered as a negative risk factor. There is a hypothesis that high concentrations of HDL in plasma are not only protective against coronary arteriopathy, but can actually induce B regression of atherosclerotic plaques (for example, see Badi on et al., 1992, Circulation 86 (Suppl III): 86-94).

Thus, HDLs have become popular as "good" cholesterol. 2. 1. TRANSPORT OF CHOLESTEROL The fat transport system can be divided into two pathways: one exogenous for cholesterol and triglycerides absorbed from the intestine, and one endogenous for cholesterol and triglycerides that enter the bloodstream of the liver and (other non-hepatic tissues. In the exogenous way, the fats of the diet are packed in lipoprotein particles called chylomicrons that enter the bloodstream and leave their triglycerides in adipose tissue (for storage) and muscle (for oxidation to supply energy). The rest of chylomicron, containing cholesteryl esters, is removed from the circulation by a specific receptor found only in liver cells. This cholesterol is then made available again for cellular metabolism or for recirculation to extrahepatic tissues such as plasma lipoproteins. 15 In the endogenous pathway, the liver secretes a large very low density lipoprotein (VLDL) particle into the bloodstream. The core of VLDL consists mainly of? triglycerides synthesized in the liver, with a smaller amount of cholesteryl esters (synthesized in the liver or recycled chylomicrons). Two predominant proteins are presented on the surface of VLDL, apoprotein B-100 and apoprotein E. When a VLDL reaches the capillaries of adipose tissue or muscle, its triglycerides are extracted giving rise to a new class of particle, diminished in size and enriched in cholesteryl esters but retaining its two apoproteins, known as intermediate density lipoprotein (IDL). f * - In humans, approximately half of the IDL particles are removed from the circulation rapidly 5 (within two to six hours of their formation), because they bind tightly to the liver cells that extract their cholesterol to make a new VLDL and bile acids. IDL particles that are not picked up by the liver remain in the circulation longer. Over time, apoprotein E dissociates from circulating particles, converting them into LDL having apoprotein B-100 as their only protein. In first lagar, the liver captures and degrades most of the cholesterol in bile acids, which are the final products of cholesterol metabolism. The uptake of cholesterol containing particles is mediated by LDL receptors, which are present in high concentrations in hepatocytes. The receiver of the > LDL binds apoprotein E and apoprotein B-100, and is responsible for binding and eliminating IDL and LDL from the circulation. However, the affinity of apoprotein E for the LDL receptor is greater than that of apoprotein B-100. As a result, LDL particles have a much larger circulating living space than IDL particles - LDL circulates for an average of two and a half days before bind to LDL receptors in the liver and other tissues.

High concentrations of serum LDL (the "bad" cholesterol) are positively associated with coronary heart disease. For example, in atherosclerosis, cholesterol derived from circulating LDL accumulates in the walls of the arteries causing the formation of voluminous plates that inhibit the flow of blood until a clot finally forms, obstructing the artery that causes an attack cardiac or cerebral vascular accident. Finally, the amount of intracellular cholesterol released from LDL controls the metabolism of cellular cholesterol. The accumulation of cellular cholesterol from VLDL and LDL controls three processes: first, it reduces the synthesis of cellular cholesterol by inhibiting the synthesis of HMGCoA reductase, a key enzyme in the cholesterol biosynthetic pathway. Second, the LDL cholesterol, incoming, favors the storage of cholesterol by activating ACAT - the cellular enzyme that converts cholesterol into cholesteryl esters that are deposited in droplets for storage. Third, the accumulation of cholesterol within the cells comes from a feedback mechanism that inhibits the cellular synthesis of the new LDL receptors. The cells, therefore, adjust their complement of the LDL receptors so that sufficient cholesterol is obtained to meet their metabolic needs, without overload, (for a review see Brown &Goldstein, In, The Pharmacological Basis Of Therapeutics, 8th edition , Goodman &Gilman, Pergamon Press, (^ NY, 1990, CH 36 pp. 874-896). 2.2. INVERSE TRANSPORT OF CHOLESTEROL In sum, the peripheral (non-hepatic) cells obtain their cholesterol from a combination of local synthesis and the uptake of preformed sterol from the VLDL and LDL. On the contrary, the reverse cholesterol transport (RCT) is the way by which cholesterol from peripheral cells can return to the liver to recycle to extrahepatic tissues, or expression to the intestine in bile, in modified form or in oxidized form as bile acids. The RCT route represents the only means of elimination of cholesterol from most extrahepatic tissues, and it is important to maintain the structure and function of most of the cells in the body. The RCT consists mainly of three steps (a) the cholesterol flow, the initial elimination of cholesterol from the different deposits of the peripheral cells; (b) cholesterol staphylation by the action of lecithin: cholesterol acyltransferase (LCAT), preventing the re-entry of effused cholesterol into the cells; and (c) uptake / delivery of HDL cholesteryl ester to liver cells. The RCT pathway is mediated by HDL. HDL is a generic term for lipoprotein particles «V that are characterized by their high density. The main lipid constituents of the HDL complexes are the 5 different phospholipids, cholesterol (ester) and triglycerides. The most prominent components of apolipoprotein are A-I and A-II that determine the functional characteristics of HDL; in addition, minor amounts of apolipoproteins C-I, C-II, C-III, D, E, J, etc. have been observed. The HDL may exist in a wide variety of different sizes and different mixtures of the aforementioned constituents depending on the / state of remodeling during the metabolic cascade of the RCT. The key enzyme involved in the RCT pathway is LCAT. The LCAT is produced mainly in the liver and circulates in the plasma associated with the HDL fraction. The LCAT converts the cholesterol coming from the cell into esters of - cholesteryl that are sequestered in the HDL destined for elimination. The ester transfer protein of cholesteryl (CETP) and the phospholipid transfer protein (PLTP) contribute to further remodeling the population of circulating HDL. CETP can move cholesteryl esters made by LCAT to other lipoproteins, particularly lipoproteins containing ApoB, such as VLDL and LDL. PLTP supplies lecithin to HDL. The triglycerides of HDL can be catabolized by the triglyceride hepatic lipase í & "Extracellular and lipoprotein cholesterol is eliminated by the liver through several mechanisms." 1 Each HDL particle contains at least one copy (and usually two to four copies) of ApoA-I. ApoA-I synthesized by the liver and small intestine as preproapolipoprotein that is secreted proprotein that dissociates rapidly to generate a mature polypeptide having 243 amino acid residues. ApoA-I consists mainly of 6 to 8 different repeats of 22 amino acids separated by a linking portion that is often proline, and in some cases consists of an elongation consisting of several residues. The ApoA-I form 3 types of stable structures with lipids: small complexes, poor in lipids known as HDL pre-β-1; flattened discoidal particles containing only polar lipids (phospholipids and cholesterol) known as "! HDL pre-ß-2; and spherical particles containing polar and non-polar lipids, known as spherical or mature HDL (HDL3 and HDL2) .The majority of HDL in the circulating population i contains ApoA-I and ApoA -II (the second most important protein HDL) and are known herein as the I fraction AI / AII-HDL of the HDL, however, the fraction of I25 the HDL containing only ApoA-I (mentioned in The present as the fraction AI-HDL seems to be more effective in the RCT.Some epidemiological studies support the hypothesis that the AI-HDL fraction is antiarterogénica [sic]. (Parra et al., 1992, Atesioscler. Thromb. 12: 701-707; Decossin et al., 1997, Eur. J. Clin. Invest. 27: 299-307). Although the mechanism for the transfer of cholesterol from the cell surface (ie, cholesterol effusion) is unknown, it is considered that the lipid-poor pre-beta-1 HDL complex is the preferred acceptor for the cholesterol transferred from the peripheral tissue involved. in the RCT. (See Davidson et al., 1994, J. Biol. Chem. 269: 22975-22982, Bieicki et al., 1992, J. Lipid Res. 33: 1699-1709, Rothblat et al., 1992, J. Lipid Res. 33: 1091-1097; and Kawano et al., 1993, Biochemistry 32: 9816-9825). During this process the recruitment of cholesterol from the cell surface, pre-beta-1 HDL is rapidly converted to HDL pre-beta-2. The PLTP may increase the rate of pre-beta-2 disc formation, but the data indicates absence of activity for the PLTP in the RCT. LCAT reacts preferably with discoidal and spherical HDLs by transferring the 2-acyl group of lecithin or other phospholipids to the free hydroxyl residue of cholesterol to generate cholesteryl esters (which are retained in the HDL) and lysolecithin. The LCAT reaction requires ApoA-I as an activator; that is, ApoA-I is the natural cofactor for LCAT. The conversion of cholesterol to its ester sequestered in HDL prevents the re-entry of cholesterol into the cell, the result being that the cholesteryl esters are destined for elimination. The cholesteryl esters in mature HDL particles in the AI-HDL fraction (ie, containing ApoA-I and not ApoA-II) are eliminated by the liver and processed in bile more efficiently than those from HDL containing ApoA-I and ApoA-II (the fraction AI / AII-HDL.) This may be due to in part, to the most efficient binding of HDL-A to the hepatocyte membrane The existence of an HDL receptor has been a hypothesis, and recently a purifying receptor, SR-BI, was identified as an HDL receptor. et al., 1996, Science 271: 518-520; Xu et al., 1997, Lipid Res. 38: 1289-1298). SR-Bl is abundantly expressed in steroidogenic tissues (for example, the adrenals), and in the liver. (Landshulz et al., 1996, J. Clin.Invest.98: 984-995; Rigotti et al., 1996, J. Biol. Chem. 271: 33545-33549). The CETP does not seem to play a primary role in the RCT, and instead is involved in the metabolism of the lipids from the VLDL and LDL. However, changes in the activity of CETP or its acceptors, VLDL and LDL, play a role in the "remodeling" of the HDL population. For example, in the absence of CETP, HDLs become larger particles that are not eliminated. (For review on RCT and HDL see Fielding &Fielding, 1995, J. Lipid Res. 36: 211-228; € • Barrans et al., 1996, Biochem. Biophys. Acta. 1300: 73-85; Hirano et al., 1997, Aterioscler. Thromb. Vasc. Biol. 17 5 (b): 1053-1059. 2. 3. CURRENT TREATMENTS FOR DISLIPOPROTEINEMIAS Different treatments are currently available to reduce cholesterol and triglycerides in serum (see, for example, Brown &Goldstein, supra). However, each has its own disadvantages and limitations in terms of efficacy, adverse effects and the population of patients who qualify for them. Resins that bind to bile acids are a class of medicines that interrupt the recycling of bile acids from the intestine to the liver; for example, cholestyramine (Questran Light®, Bristol-Myers Squibb), and colestipol hydrochloride (Colestid®, The Upjohn Company). When they are taken > orally, these positively charged resins bind to the bile acids with negative charge in the intestine. Because the resins can not be absorbed from the intestine, they are excreted carrying the bile acids with these. The use of these resins, however, in the best case only reduces serum cholesterol concentrations in approximately 20%, and are associated with gastrointestinal side effects, including constipation and certain vitamin deficiencies. In addition, since resins bind to other medications, other oral administrations must be taken at least one hour before or four to six hours after ingestion of the resin; thus, complicating the drug regimens of cardiac patients. Statins are cholesterol-lowering compounds that block cholesterol synthesis by inhibiting AMGCoA reductase, the key enzyme involved in the cholesterol biosynthetic pathway. Statins, for example, lovastatin (Mevácor®, Merck &Co., Inc.) and pravastatin (Pravachol®, Bristol-Myers Squibb Co.) are sometimes used in combination with resins that bind to bile acid. Statins significantly reduce serum cholesterol and LDL levels, and slow the progression of coronary atherosclerosis. However, serum HDL cholesterol levels only increase slightly. The mechanism of the LDL-lowering effect may include reducing the concentration of VLDLs and inducing cellular expression of the LDL receptor, resulting in reduced production and / or increased catabolism of LDL. Side effects, including liver and kidney dysfunction, are associated with the use of these medications (Physicians Desk Reference, Medical Economics Co., Inc., Montvale, N. J. 1997). Currently, the FDA has approved atorvasatatin [sic] (an inhibitor of HMGCoA reductase developed by Parke-Davis) (Warner Lambert) for the market in order to treat rare but urgent cases of familial hypercholesterolemia (1995, Scrip 20 ( 29): 10). Niacin, or nicotinic acid, is a water-soluble vitamin B complex used as a dietary supplement and anti-hyperlipidemic compound. Niacin decreases VLDL production and is effective in reducing LDL. In some cases, it is used in combination with resins that "bind to bile acids." Niacin can increase HDL when used in adequate doses, however, its usefulness is limited by serious side effects when used at such doses. Fibrates are a class of lipid-lowering medications used to treat different forms of hyperlipidemia (ie, elevated triglycerides in serum) that may also be associated with hypercholesterolemia, and fibrates seem to reduce the VLDL fraction and moderately increase HDL. However, the effects of these drugs on serum cholesterol are variable: in the United States, fibrates have been approved for use as antilipidemic drugs, but have not received approval as hypercholesterolemia compounds., clofibrate (Atromid-S®, Wyeth-Ayerest Laboratories) is an antilipidemic compound that acts (by an unknown mechanism) to reduce serum triglycerides by reducing the VLDL fraction, although serum cholesterol can be reduced in certain subpopulations of patients, the biochemical response to the medication is variable, and it is not always possible to predict which patients will obtain favorable results.Atromid-S® has not been shown to be effective for the prevention of coronary heart disease.10 The chemical and pharmacologically related drug, ge fibrozil (Lopid® Parke-Davis) is a lipid-regulating compound that moderately decreases serum triglycerides and VLDL cholesterol, and moderately increases HDL cholesterol, HDL2 and HDL3 subfractions, and as ApoA-I and A-II [sic] (ie, fraction AI / AII-HDL). However, the response to lipids is heterogeneous, especially among different patient populations. In addition, although the prevention of coronary heart disease was observed in male patients between 40-55 without If there is a history or symptoms of existing coronary heart disease, it is not clear until these findings can be extrapolated to other patient populations (for example, women, older or younger women). In fact, no efficacy was observed in patients with heart disease established coronary. Serious side effects are associated with the use of fibrates including toxicity as a malignancy, (especially gastrointestinal cancer), gallbladder disease and an increased incidence of non-coronary mortality. These drugs are not indicated for the treatment of patients with high concentrations of LDL or low concentrations of HDL as their only lipid abnormality (Physicians' Desk Reference, 1997, Medical Economics Co., Inc., Montvale, N.J.). 10 Oral estrogen replacement therapy can be considered to moderate hypercholesterolemia in women in the post-menopausal period. However, increases in HDL can be accompanied by an increase in triglycerides. The treatment of estrogen is, of course, limited to a specific patient population (post-encephalic) and is associated with serious side effects including the induction of malignant neoplasms, gallbladder disease, thromboembolic disease, hepatic adenoma, high blood pressure, glucose intolerance and hypercalcemia. In this way, there is a great need to develop safe drugs that are effective in reducing serum cholesterol, increasing serum HDL concentrations, preventing coronary heart disease and / or treating existing diseases, especially atherosclerosis. 2. 4. ApoA-I AS AN OBJECTIVE None of the drugs currently available to reduce cholesterol safely elevate HDL concentrations and stimulate the RCT, most of which seems to operate on the cholesterol transport pathway modulating dietary intake, recycling, cholesterol synthesis and the VLDL population. Although it is desirable to find medicines that stimulate the effusion and elimination of cholesterol, there are some potential targets in the RCT, for example, LCAT, HDL and its different components (ApoA-I, ApoA-II and phospholipids), LTP and CETP, and the objective that should be most effective in obtaining desirable lipoprotein profiles and protective effects is not known. The disorder of any The individual component in the RCT pathway eventually affects the composition of circulating lipoprotein populations, and the efficiency of the RCT. Some lines of evidence based on in vivo data implicate HDL and its component main protein, ApoA-I in the prevention of atherosclerotic lesions, and potentially, the regression of plaques, making these targets attractive for therapeutic intervention. First, there is an inverse correlation between serum ApoA-I concentrations (HDL) and atherogenesis in men (Gordon &Rifkind, 1989, N.

Eng. J. Med. 321: 1311-1311-1316; Gordon et al., 1989, Circulation 79: 8-15). Indeed, HDL-specific subpopulations have been associated with a reduced risk for atherosclerosis in humans (Miller, 1987, Amer. Heart 5 113: 589-597; Cheung et al., 1991, Lipid Res. 32: 383- 394); Fruchart & Ailhaud, 1992, Clin. Chem. 38: 79). Second, animal studies support the protective activity of ApoA-I (HDL). The treatment of rabbits fed cholesterol, with ApoA-I or HDL reduced the development and progress of plaques (fat plates) in rabbits fed cholesterol. (Koizumi et al., 1988, J. Lipid Res. 29: 1405-1415; Badimon et al., 1989, Lab Invest., 60: 455-461; Badimon et al., 1990, J. Clin. Invest. 1234-1241). However, the effectiveness varied depending on the source of HDL (Beitz et al., 1992, Protaglandins, Leukotrienes and Essential Fatty Acids 47: 149-152; Mezdour et al., 1995, Atherosclerosis 113: 237-246). ) Third, direct evidence for the activity of ApoA-I was obtained from expents involving transgenic animals. The expression of the human gene for ApoA-I transferred to mouse genetically predisposed to diet-induced atherosclerosis protected against the development of aortic lesions (Rubin et al., 1991, Nature 353: 265-267). It was also shown that the ApoA-I transgene suppresses atherosclerosis in ApoE deficient mice and Apo (a) transgenic mice (Paszty et al., 1994, J. Clin.Invest.94: 899-903; Plump et al., 1994, Proc. Nati. Tl Acad Sci. USA 91: 9607-9611, Lin et al., 1994, J. Lipid.

Res. 35: 2263-2266). Similar results were observed in transgenic rabbits expressing for human ApoA-I (Duverger, 1996, Circulation 94: 713-717; Duverger et al., 1996, Atscler. Thromb. Vasc. Biol. 16: 1424-1429) and in transgenic rats where high concentrations of human ApoA-I protected against atherosclerosis and inhibited restenosis after balloon angioplasty (Burkey et al., 1992, Circulation, Supplement I, 86: 1-472, Abstract No. 1876, Burkey et al., 19 * 95, J. Lipid Res. 36: 1463-1473) . HDL-AI appears to be more effective in RCT than fraction AI / AII-HDL. Studies with transgenic mice for ApoA-I Human or ApoA-I and ApoA-II (AI / AII) showed that the protein composition of HDL significantly affects its activity, AI-HDL is more anti-atherogenic than AI / AII-HDL (Schultz et al., 1993 , Nature 365: 762-764). Parallel studies involving transgenic mice expressing for the human LCAT gene show that moderate increases in LCAT activity significantly change lipoprotein cholesterol concentrations, and that LCAT has a significant preference for HDL containing ApoA-I (Francone et al., 1995, J. Clinic Invest 96: 1440- 25 1448; Beard et al., 1997, Nature Medicine 3, 7: 744-749).

Although these data support a significant activity for ApoA-I in the activation of LCAT and the stimulation of t RCT, additional studies demonstrate a more complicated scenario: A main component of HDL that modulates the effusion of cholesterol in the cell is the phospholipid ( Fournier et al., 1996, J. Lipid Res. 37: 1704-1711). In view of the potential activity of HDL, ie, ApoA-I and its associated phospholipid, in the protection against atherosclerotic disease, clinical tests in humans using recombinantly produced ApoA-I were started, discontinued and apparently started again by UCB Belgium (Pharma Projects, [sic] October 27, 1995; IMS R &D Focus, June 30, 1997; Drug Status Update, 1997 , Atherosclerosis 2 (6): 261-265); See also M. sson in Congress, "The Role of HDL in Disease Prevention ", Nov. 7-9, 1996, Fort Worth, Lacko &Miller, 1997, J. Lip. Res. 38: 1267-1273; and WO 94/13819) and were started and discontinued by Bio-Tech (Pharmaprojects, April 7, 1989). The tests were also tried using ApoA-I to treat septic shock (Opal, "Reconstituted HDL as a Tratment Strategy for Sepsis", IBCs 7th International Conference on Sepsis, April 28-30, 1997, Washington, D.C. Gouni et al., 1993, J. Lipid Res. 94: 139-146; Levine WO96 / 04916). However, there are many doubts associated with the production and use of ApoA-I making it less than ideal as a drug, for example, ApoA-I is a large protein that is difficult and expensive to produce; significant problems in manufacturing and reproducibility with respect to stability during storage, delivery of an active product and half-life in vivo must be overcome. In view of these drawbacks attempts have been made to prepare peptides that mimic ApoA-I. Since the key activities of ApoA-I have been attributed to the presence of multiple repeats of a unique secondary structural feature in the protein, a helix a, antipathic, class A (Segrest, 1974, FEBS Lett 38: 247-253), most of the efforts to design peptides that mimic the activity of ApoA-I have focused on designing peptides that form helices a, antipathic, type class A. The helices to antipathic, of class A type, are unique in that the amino acid residues with positive charge are ) grouped in the hydrophobic-hydrophilic interface and the negatively charged amino acid residues are grouped in the hydrophilic face center. In addition, class A helical peptides have a hydrophobic angle of less than 180 ° C (Segrest et al., 1990, PROTEINS: Structure, Function and Genetics 8: 103-117). Initial de novo strategies for designing ApoA-I imitations were not based on the primary sequences of the apolipoproteins, natural, but rather in the incorporation of these unique class A helix characteristics in the sequences of the t peptide analogues as well as some of the properties of the ApoA-I domains (see, for example, example, Davidson et al., 1996, 5 Proc. Nati, Acad. Sci. USA: 93: 13605-13610, Rogers et al., 1997, Biochemistry 36: 288-300, Lins et al., 1993, Biochim. Acta biomembranes 1151: 137-142; Ji and Jonas, 1995, J. Biol. Chem. 270: 11290-11297; Collet et al., 1997, Journal of Lipid Research, 38: 634-644; Sparrow and Gotto, 1980, Ann. N.Y. Acad. Sci. 348: 187-211; Sparrow and Gotto, 1982, CRC Crit. Rev. Biochem ,. 13: 87-107; Sorci-Thomas et al., 1993, J. Biol. Chem. 268: 21403-21409; Wang et al., 1996, Biochimin. Biophys. Act 174-184; Munnich et al., 1992, J. Biol. Chem. 267: 16553-16560; Holvoet et al., 1995, Biochemistry 34: 13334-13342; Sorci-Thomas et al., 1997, J.

Biol. Chem. 272 (11): 7278-7284; and Frank et al., 1997, Biochemistry 36: 1798-1806). In one study, Fukushima et al. Synthesized a 22 residue peptide composed "completely of the Glu residues, Lys, and Leu arranged periodically to form an antipathic helix with equal hydrophobic and hydrophobic faces ("LEK peptide") (Fukushima et al., 1979, J. Amer. Chem. Soc. 101 (13): 3703-3704; Fukushima et al., 1980, J. Biol. Chem. 255: 10651-10657;). The ELK peptide shares 41% of the homology of the sequence with fragment 198-219 of ApoA-I. When studied by quantitative ultrafiltration, gel permeation chromatography and circular dichroism, it was shown that this ELK peptide associates effectively with phospholipids and mimics some of the physical and chemical properties of ApoA-I (Kaiser et al., 1983, Proc. Nati, Acad. Sci. USA 80: 1137-1140, Kaiser et al., 1984, Science 223: 249-255, Fukushima et al., 1980, supra, Nakagawa et al., 1985, J. Am. Chem. Soc. 107: 7087-7092). Yokoyama et al concluded from these studies that the crucial factor for the activation of LCATs is simply the presence of a rather large antipathic structure (Yokoyama et al., 1980, J. Biol. Chem. 255 (15): 7333-7339). Subsequently a dimer of this 22 residue peptide was found which more closely mimics ApoA-I than the monomer; based on these results, it was suggested that the 44-mer that is penetrated in half by a propeller breaker (Gly or Pro), represents the minimum functional domain in ApoA-I (Nakagawa et al., 1985, supra). Another study involved model antipathetic peptides known as "LAP peptides" (Pownall et al., 1980, Proc. Nati. Acad Sci. In USA 77 (6): 3154-3158; Sparrow et al., 1981, In: Peptides : Synthesis-Structure-Function, Roch and Gross, Eds., Pierce Chem. Co., Rockford, IL, 253-256). Based on lipid binding studies with fragments of native apolipoproteins, some LAP peptides were designated, designated LAP-16, LAP-20 and LAP-24 (containing 16, 20 and 24 amino acid residues, respectively). These? • Model antipathetic peptides do not share sequence homology with apolipoproteins and were designated by having hydrophilic faces organized in a different form to helical, antipathetic, class A -type domains associated with apolipoproteins (Segrest et al., 1992, J. Lipid Res. 33: 141-166). From these studies, the authors concluded that a minimum length of 20 residues is necessary to confer lipid binding properties for model antipathetic peptides. Studies with LAP 20 mutants containing a proline residue at different positions in the sequence indicated that there is a direct relationship between the binding to lipids and activation of the LCAT, but that the helical potential of a peptide alone does not give rise to the activation of the LCAT (Ponsin et al., 1986 J. Biol. Chem. 261 (20): 9202-9205). In addition, the presence of this propeller breaker (Pro) about half the peptide reduces its affinity for the phospholipid surfaces as well as their ability to activate LCAT. Although it was shown that certain LAP peptides bind phospholipids (Sparrow et al., Supra), there is controversy as to the extent to which LAP peptides are helical in the presence of lipids (Buchko et al., 1996, J. Biol. Chem. 271 (6): 3039-3045; Zhong et al., 1994, Peptide Research 7 (2): 99-106). Segrest et al. Have synthesized peptides composed of? _ * 18 to 24 amino acid residues that do not share sequence homology with the helices of ApoA-I (Kannelis et al., 1980, J. Biol. Chem. 255 (3 ): 11464-11472; Segrest et al., 1983, J. Biol. Chem. 258: 2290-2295). The sequences were specifically designed to mimic the antipathetic helical domains of class A interchangeable apolipoproteins in terms of hydrophobic momentum (Eisenberg et al., 1982, Nature 299: 371-374) and load distribution (Segrest et al., 1990, Proteins 8: 103-117; US Patent No. 4,643,988). An 18-residue peptide, the "18A" peptide was designed to be a class A helix, model (Segrest et al., 1990, surpra).

Studies with these peptides and other peptides having an inverted charge distribution, such as the "18R" peptide, have consistently shown that the distribution of the charge? it is crucial for the activity; the peptides with an inverted charge distribution show a decrease in the Affinity to lipids relative to imitations 18A class A, and a lower helical content in the presence of lipids (Kanellis et al, 1980, J. Biol. Chem. 255: 11464-11472; Anantharmaiah et al., 1985, J Biol. Chem. 260: 10248-10255; Chung et al., 1985, J. Biol. Chem. 260: 10256-1026; Epand and col., 1987, J. Biol. Chem. 262: 9389-9396; Anantharamaiah et al., 1991, Adv. Exp. Med. Biol. 285: 131-140). Other synthetic peptides not sharing sequence homology with apolipoproteins that have been proposed with limited success include the dimers and trimers of peptide 18A (Anantharamaih et al., 1986, Proteins of Biological Fluids 34: 63-66), the GALA and EALA peptides (Subbarao et al., 1988, Proteins: Structure, Function and Genetics 3: 187-198) and the ID peptides (Labeur et al., 1997, Atherosclerosis, Thrombosis, and Vascular Biology 17: 580-588) and the 18AM4 peptide (Brasseur et al., 1993, Biochem.

Biophys. Acta 1170: 1-7). / A "Consensus" peptide containing residues of 22 amino acids based on the sequence of human ApoA-I has also been designed (Anantharamaiah et al., 1990, Arteriosclerosis 10 (1): 95-105; Venkatachalapathi et al., 1991, Mol. Conformation and Biol. Interactions, Indian Acad.

Sci. B: 585-596). The sequence was constructed by identifying the most prevalent residue in each position of the hypothetical ApoA-I helices. Like the peptides described above, the helix formed by this peptide has positively charged amino acid residues grouped at the hydrophilic interface: hydrophobic, negatively charged amino acid residues grouped in the center of the hydrophilic face and hydrophobic angle less than 180 ° . Although a dimer of this peptide is somewhat effective in the activation of LCAT, the monomer exhibited poor lipid binding properties (Venkatachalapathi et al., 1991, supra). Based mainly on in vitro studies with the (< peptides described above, a series of "rules" 5 have emerged to designate peptides that mimic the ApoA-I function.) Significantly, an antipathic helix having positively charged residues, grouped at the interface, is considered. hydrophilic-hydrophobic and the negatively charged amino acid residues grouped in the center of the hydrophilic face are required for lipid affinity and activation of LCAT (Venkatachalapathi et al., 1991, supra). Anantharamaiah et al. Have also indicated that the negatively charged Glu residue at position 13 of the 22-mer consensus peptide, which is located within the face Hydrophobic a-helix, plays an important role in the activation of the LCAT (Anantharamaiah et al., 1991, supra). In addition, Brasseur has indicated that a hydrophobic angle (pho angle) of less than 180 ° is required for the > optimal stability of the lipid-apolipoprotein complex, and also represents the formation of discoidal particles having peptides around the edge of a lipid bilayer (Brasseur, 1991, J. Biol. Chem. 66 (24): 16120-16127). Rosseneu et al. Have also insisted that a hydrophobic angle of less than 180 ° is required for the activation of the LCAT (W093 / 25581).

However, despite these "rules" to date, none have designated or produced a peptide as active as ApoA-I, at best having less than 40% of ApoA-I activity when measured by the activation test of the LCAT described herein. None of the "mimetic" peptides described in the literature have been shown to be useful as medicaments. In view of the aforementioned, there is a need for a development of a stable ApoA-I agonist that mimics the activity of ApoA-I, whose production is relatively simple and cost-effective. However, the "rules" to designate effective ApoA-I imitations have not been undisclosed [sic] and the principles for inventing organic molecules with ApoA-I function are unknown.

COMPENDIUM OF THE INVENTION The invention relates to ApoA-I agonists capable of forming helices to antipathic that mimic the activity of ApoA-I, with specific activities, ie, activity units (LCAT activation) / unit of mass) [sic], approaching or exceeding that of the native molecule. In particular, the ApoA-I agonists of the invention are peptides or peptide analogues that: form antipatic helices (in the presence of lipids), bind to lipids, form pre-β or HDL type complexes, activate LCAT, increase the concentrations of the HDL fractions in serum and favor the effusion of cholesterol. The invention is based, in part, on the design and discovery of the applicants of the peptides that mimic the function of ApoA-I. The peptides of the invention were designed based on the assumed helical structure and the antipathetic properties of the consensus sequence of 22 amino acids that was obtained from helical repeats of ApoA-I. What is surprising, the peptides of the invention have a specific activity well above that reported for peptides derived from ApoA-I described in the literature. In fact, some of the embodiments of the invention approach 100% of the activity of native ApoA-I, while the superagonists described herein exceed the specific activity of ApoA-I. The invention is illustrated by means of working examples which describe the structure, preparation and use of the particular antipyatic peptides which form helices (in the presence of lipids), bind to lipids, form complexes and increase the activity of LCAT. Based on the structure and activity of the exemplified embodiments, the applicants have invented a series of "rules" that can be used to design altered or mutated forms that are also within the scope of the invention.

The invention also relates to pharmaceutical formulations containing such ApoA-I agonists (such as peptides or peptide / lipid complexes) as the active ingredient, as well as methods for the preparation of such formulations and their use to treat diseases associated with dyslipoproteinemia (for example, cardiovascular diseases, atherosclerosis, metabolic syndrome), restenosis or endotoxemia. (for example, septic shock). 3. 1. ABBREVIATIONS As used herein, the abbreviations for the genetically encoded L-enantiomeric amino acids are conventional and are as follows: The abbreviations used for the D-enantiomers of the genetically encoded amino acids are lowercase letters equivalent to the symbols of a letter. For example, "R" designated L-arginine and "r" designates D-arginine. / 3. 2. DEFINITIONS As used herein, the following terms shall have the following meanings: "Alkyl": refers to a branched chain hydrocarbon radical, linear or cyclic, saturated. Common alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, and the like. In the preferred embodiments, the alkyl groups are alkyl (from C? -C6). "Alkenyl": refers to a branched chain, straight or cyclic hydrocarbon radical, unsaturated having at least one carbon-carbon double bond. The radical can be in the cis or trans conformation with respect to the double (s) bond (s). Common alkenyl groups include, but are not limited to, ethenyl, propenyl isopropenyl, butenyl, isobutenyl, tert-butenyl, pentenyl, hexenyl and the like. In preferred embodiments, the alkenyl group is Ci-Cß alkenyl). "Alkynyl": refers to a branched, linear or cyclic hydrocarbon radical, unsaturated, having at least one carbon-carbon triple bond. Common alkynyl groups, include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like. In the preferred embodiments, the alkynyl group is alkynyl (of Ci-Ce). "Aryl": refers to a cyclic, unsaturated hydrocarbon radical having a p-conjugated electron system. Common aryl groups include, but are not limited to, penta-2,4-diene, phenyl, naphthyl, anthracyl, azulenyl, chrysenyl, coronenyl, fluoroantenyl, indacenyl, indenyl, oleyl, perylenyl, phenalenyl, phenanthrenyl, picenyl, pleiadenyl, pyrenyl, pyrantrenyl, rubicenil and the like. In the preferred embodiments, the aryl group is aryl (C5-C20). being C5-C10 particularly preferred. "Alkaryl": refers to a straight chain alkyl, alkenyl or alkynyl group in which one of the hydrogen atoms attached to a terminal carbon is substituted with an aryl moiety. Common alkaryl groups include, but are not limited to, benzyl, benzylidene, benzylidino, benzenebenzyl, naphthenobenzyl and the like. In the ll preferred embodiments, the alkaryl group is C? -C26 alkaryl / that is, the alkyl, alkenyl or alkynyl portion of the alkaryl group is Ci-Cß and the aryl portion is C5-C20- In the embodiments particularly Preferred, the alkaryl group is C6-C13 alkaryl, that is, the alkyl, alkenyl or alkynyl portion of the alkaryl group is C1-C3 and the aryl portion is C5-C10. "Heteroaryl": refers to an aryl portion in which one or more carbon atoms is substituted with another atom, such as N, P, O, S, As, Se, Si, Te, etc. Common heteroaryl groups include, but are not limited to, acridarsin, acridine, arsantridine, arsindol, arsindoline, carbazole, ß-carboline, chromene, cinolino, furan, imidazole, indazole, indole, indolizine, isoarsindole, isoarsinoline, isobenzofuran, isochromen, isoindole, isophosphoindole, ) isophosphoindoline, isoquinoline, isothiazole, isoxasol, naphthyridine, perimidine, [sic], phenanthridine, phenanthroline, Phenazine, phosphoindol, phosphinoline, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, selenophene, telurofen, thiophene, and xanthene. In the preferred embodiments, the heteroaryl group is a 5- to 20-membered heteroaryl with 5 to 10 membered aryl being particularly preferred. "Alk-heteroaryl": refers to an alkyl group, alkenyl, or straight chain alkynyl wherein one of the hydrogen atoms attached to a terminal carbon atom is substituted with a heteroaryl portion. In preferred embodiments, the alkoheteroaryl group is alkenyl of 6 to 26 members, that is, the alkyl, alkenyl or alkynyl portion of the alkyteroaryl is Ci-Cg and the heteroaryl is 5- to 20-membered heteroaryl. In the particularly preferred embodiments, the "heteroaryl" is alkenyl of 6 to 13 members, that is, the alkyl, alkenyl or alkynyl portion is a 5- to 10-membered heteroaryl. "Alkyl, alkenyl, alkynyl, aryl, alkaryl, "Heteroaryl, or substituted alkyl-heteroaryl": refers to an alkyl, alkenyl, alkynyl, aryl, alkaryl, heteroaryl or alk-heteroaryl group in which one or more other I hydrogen is substituted with another substituent. Preferred substituents include -OR, -SR, -NRR, -N02, -CN, Halogen, -C (0) R, -C (0) OR and -C (0) NR, wherein each R is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, heteroalkyl or alk-heteroaryl. 4. BRIEF DESCRIPTION OF THE FIGURES 25 FIGURE IA is a diagram of the Schiffer-Edmundson helical wheel of an idealized antipathetic helix in which clear circles represent hydrophilic amino acid residues and shaded circles represent hydrophobic amino acid residues. FIGURE IB is a diagram of the helical network of the idealized antipathetic helix of FIGURE IA. FIGURE 1C is a diagram of the helical cylinder of the idealized antipathetic helix of FIGURE IA. FIGURE 2A is a diagram of the Schiffer-Edmundson helical wheel of the core peptide of structure (I) illustrating the amphipathicity of the helix (light circles represent hydrophilic amino acid residues, shaded circles represent hydrophobic amino acid residues, and partially shaded circles represent residues of hydrophilic or hydrophobic amino acids). FIGURE 2B is a diagram of the helical network of the core peptide of structure (I) illustrating the hydrophobic face of the helix. FIGURE 2C is a diagram of the helical network of the core peptide of structure (I) illustrating the hydrophilic face of the helix. FIGURE 3A is a diagram of the helical network illustrating the hydrophilic face of the Segrest consensus 22-mer peptide (PVLDEFREKLNEELEALKQKLK; SEQ ID NO: 75). FIGURE 3B is a diagram of the helical network illustrating the hydrophilic face of the exemplary core peptide 146 (PVLELFENLLERLLDALQKKLK; SEQ ID NO: 146). FIGURE 4A is a diagram of the helical network illustrating the hydrophobic face of the 22-mer Segrest consensus peptide (SEQ ID NO: 75). FIGURE 4B is a diagram of the helical network illustrating the hydrophobic face of the exemplary core peptide 146 (SEQ ID NO: 146). FIGURE 5A is a diagram of the Schiffer-Edmundson helical wheel of the 22-mer Segrest consensus peptide (SEQ ID NO: 75). FIGURE 5B is a diagram of the Schiffer-Edmundson helical wheel of the exemplary core peptide 146 (SEQ ID NO: 146). FIGURE 6 is a computer model of two peptides 146 (SEQ ID NO: 146) arranged in an antiparallel mode in which the Glu-7 and Gln-18 residues are highlighted to illustrate the ability of these two peptides to form Intermolecular hydrogen bonds when they bind to lipids. FIGURE 7A illustrates a branched network of the tertiary order of the invention. FIGURE 7B illustrates a quaternary branched network of the invention. FIGURE 7C illustrates a mixed order branched network of the invention. FIGURE 7D illustrates branching "tree of Lys" networks of the invention. FIGURE 8A is a graph illustrating the differences between the observed chemical shifts and the chemical shifts Ha of random tabulated coiling for peptide 146 (SEQ ID NO: 146) and the Segrest consensus 22-mer peptide (SEQ ID NO. : 75). FIGURE 8B is a graph illustrating the differences between the chemical shifts of the amide proton observed and the chemical shifts of the amide proton from the coil randomly tabulated for peptide 146 (SEQ.

ID NO: 146) and the Segrest consensus 22-mer peptide (SEQ ID NO: 75). FIGURE 8c is a graph comparing the chemical shifts of the secondary amine proton observed for peptide 146 (SEQ ID NO: 146) (F) with those of an idealized (?) Helix (in the idealized helix, the recirculated hydrophilic are represented as clear circles, hydrophobic recumbents as dark circles) . FIGURE 9 is a graph illustrating the profile of a rabbit lipoprotein injected with 8 mg / kg body weight of peptide 146 (SEQ ID NO: 146) (in the form of peptide / DPPC complexes). FIGURE 10A is a drawing depicting the different aggregation states and peptide-lipid complexes that can be obtained with the ApoA-I agonists of the invention. Left: Process of ultimerization of the peptides resulting from the interaction of different peptide helices and giving rise to the formation of oligomers under concentration conditions, pH and defined ionic concentration of the peptide. Center: The interaction of the peptides (in any of these states of aggregation) with lipid entities (as can the SUV) gives rise to the reorganization of lipids. Right: By changing the lipid: peptide molar ratio, it is possible to obtain different types of peptide-lipid complexes, from lipid-peptide comixes in low lipid-peptide proportions, to discoidal particles and finally to large multilamellar complexes in lipid: peptide proportions greater. FIGURE 10B illustrates the generally accepted model for discoidal peptide-lipid complexes formed in a defined range of lipid: peptide ratios. Each peptide that surrounds the edge of the disc is in greater contact with its two closest neighbors.

. DETAILED DESCRIPTION OF THE INVENTION The ApoA-I agonists of the invention mimic the function and activity of ApoA-I. These form antiphatic helices (in the presence of lipids), bind to lipids, form pre-ß or HDL-like complexes, activate LCAT, increase the HDL concentration in serum and favor the effusion of cholesterol. The biological function of the peptides correlates with their helical structure, or the conversion to helical structures in the presence of lipids. The ApoA-I agonists of the invention can be prepared in stable unit or bulk dosage forms, for example, lyophilized products that can be reconstituted before use in vivo or reformulated. The invention includes pharmaceutical formulations and the use of these preparations in the treatment of hyperlipidemia, hypercholesterolemia, coronary heart disease, atherosclerosis and other conditions such as endotoxemia causing septic shock. The invention is illustrated by working examples which demonstrate that the ApoA-I agonists of the invention are extremely effective in the activation of LCAT, and thus favor the RCT. The use of the ApoA-I agonists of the invention in vivo in animal models gives rise to an increase in the concentration of HDL in serum. The invention is set forth in more detail in the following subsections, which describe: the composition and structure of the peptide agonists of ApoA-I; the structural and functional characterization; the methods of preparation of bulk formulations and in unit dosages; and the methods of use. . 1 STRUCTURE AND FUNCTION OF THE PEPTIDE The ApoA-I agonists of the invention are generally peptides, or analogs thereof, which are capable of forming antipathetic alpha helices in the presence of lipids and which mimic the activity of ApoA-I. Agonists have as their main characteristic a "core" peptide composed of 15 to 29 amino acid residues, preferably 22 amino acid residues, or an analogue thereof wherein at least one amide bond in the peptide is substituted with a substituted amide , an isostere of an amide or a mimetic amide. The ApoA-I agonists of the invention are based, in part, on the surprising discovery of applicants that by altering certain amino acid residues in the primary sequence of the 22-mer consensus sequence of Venkatachalapathi et al., 1991, Mol. Conformation and Biol. Interactions, Indian Acad. Sci. B: 585-596 (PVLDEFREKLNEELEALKQKLK; SEQ ID NO: 75; hereinafter "22-th Segrest consensus" or "22-mere consensus") that were considered crucial for activity produces synthetic peptides that exhibit activities that are approaching, or in some modalities still exceed, the activity of native ApoA-I. In particular, applicants have discovered that substituting three charged amino acid residues in the Segrest consensus 22-mer peptide (Glu-5, Lys-9 and Glu-13) with a hydrophobic Leu residue provides the peptides that mimic the properties structural and functional aspects of ApoA-I in a manner unprecedented in the art. While not intending to adhere to any specific theory, it is considered that the helix formed by the ApoA-I agonists of the invention more closely mimic the structural and functional properties of the antipatic helical regions of native ApoA-I which are important in effecting the lipid binding, cholesterol effusion and activation of LCAT compared to helix a formed by the ApoA-I mimetic peptides described in the literature, thereby giving rise to peptides that exhibit ApoA-I-like activity greater than those other peptides. In fact, while many of the ApoA-I agonists of the invention approach, and in some embodiments still exceed, the activity of ApoA-I, to date the peptide that best mimics ApoA-I described in the literature , the 18AM4 peptide. (EWLEAFYKKVLEKLKELF; SEQ ID NO: 246) (Corinjn and .col., 1993, Biochim Biophys, Acta 1170: 8-16, Labeur et al., October 1994, Arteriosclerosis: Abstract Nos. 186 and 187) and peptide 18AM4 N-acetylated, C-amidated (SEQ ID NO: 239) (Brasseur, 1993, Biochim, Biophys, Acta 1170: 1-7) exhibit less than 4% and 11%, respectively, of the f ~ t activity of ApoA- I when measured by the activation test of the LCAT that is described in this. In an illustrated embodiment of the invention, the core peptides (or analogs thereof) that make up the ApoA-I agonists of the invention have the following structural formula (I): X-X2-X3-X4-X5-X6-X6-X7-X8-X9-Xl0-Xll-Xl2 ~ Xl3-Xl4-Xl5-Xl6"Xl7-Xl8 ~ Xl9- X20" X21 ~ X22 where: Xi is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N), Asp (D) 15 or D-Pro (p); X2 is an aliphatic amino acid; X3 is Leu (L) or Phe (F); X4 is Glu (E); X5 is an aliphatic amino acid; 20 X6 is Leu (L) or Phe (F); X7 is Glu (E) or Leu (L); X8 is Asn (N) or Gln (Q); Xg is Leu (L); Xio is Leu (L), Trp (W) or Gly (G); 25 Xn is an acidic amino acid; Xi2 is Arg (R); Xis is Leu (L) or Gly (G); The core peptides of structure (I) are defined, in part, in terms of the amino acids of designated classes. The definitions of the different designated classes are provided infra in connection with the description of the mutated or altered structure (I) modalities. In the core peptides of structure (I), the symbol "-" between amino acid residues Xn generally designates a constitutive linkage function of the main chain. Thus, the symbol "-" usually represents a peptide bond or amide bond (-C (O) NH-). However, it should be understood that the present invention contemplates peptide analogs wherein one or more amide bonds is optionally substituted with a different amide bond, preferably a substituted amide or an amide isostere. Thus, although the different Xn residues within the structure (I) are generally described in terms of amino acids, and the preferred embodiments of the invention are exemplified by means of the peptides, one skilled in the art will recognize that in the embodiments having links no amide, the term "amino acid" or "residue" as used herein refers to other portions - • bifunctional carriers of similar groups in structure to 5 amino acid side chains. Substituted amides generally include, but are not limited to, groups of the formula -C (0) NR-, where R is Ci-Cd alkyl, substituted Ci-C alquilo alkyl, Ci-Cd alkenyl, Ci-alkenyl, Substituted Cß, Ci-Ce alkynyl, Substituted Ci-Cβ alkynyl, C5-C20 aryl substituted C5-C20 aryl, C6-C26 alkaryl substituted C6-C26 alkaryl, 5- to 20-membered heteroaryl, substituted 5- to 20-membered heteroaryl, alky-heteroaryl from 6 to 26 members and alk-heteroaryl from 6 to 26 members, substituted. The amide isosterers generally include, but are not limited to, -CH2NH-, -CH2S-, -CH2CH2-, -CH = CH- (cis and trans), -C (0) CH2-, -CH (OH) CH2- and -CH2SO-. The compounds having these non-amide linkages and the methods for preparing these compounds are well known in the art (see, for example, Spatola, March 1983, Vega Data vol. 1, publication 3; Spatola, 1983, "Peptide Backbone Modifications" In: Chemistry and Biochemistry of Amino Acids Peptides and Proteins, Weinstein, ed., Marcel Dekker, New York, p. 267 (general review); Morley, 1980, Trends Pharm.

Sci. 1: 463-468; Hudson et al., 1979, Int. J. Prot. Res. 14: 177-185 (-CH2NH-, -CH2CH2-); Spatola et al., 1986, Life Sci. 38: 1243-1249 (-CH2S); Hann, 1982, J. Chem. Soc. Perkin Trans. I. 1: 307-314 (-CH = CH-, cis and trans); Al Quist et al., 1980, J. Med. Chem. 23: 1392-1398 (-C0CH2-); Jennings-White et al., Tetrahedron. Lett. 23: 2533 (-COCH2-); European Patent Application EP 45665 (1982) CA 97: 39405 (-CH (OH) CH2 ~); Holladay et al., 1983, Tetrahedron Lett. 24: 4401-4404 (-C (OH) CH2-); and Hruby, 1982, Life Sci. 31: 189-199 (-CH2-S-). In addition, one or more amide linkages may be substituted with peptide mimetic or amido mimetic portions that do not significantly interfere with the structure or activity of the peptides. Suitable amido mimetic portions are described, for example, in Olson et al., 1993, J. Med. Chem. 36: 3039-3049. A crucial feature of the core peptides of the structure (I), is its ability to form an antipathetic helix in the presence of lipids. By antipathic it is understood that the a helices have opposite hydrophilic and hydrophobic faces oriented along their longitudinal axis, i.e. one face of the propeller projects primarily hydrophilic side chains while the opposite face projects mainly hydrophobic side chains. FIGURES IA and IB present two illustrative views of the opposite hydrophilic and hydrophobic faces of an antipathetic, idealized, exemplary helix. FIGURE 1A is a diagram of the helical wheel of Schiffer-Edmundson (Schiffer and Edmundson, 1967, Biophys, J. 7: 121-135). In the wheel, the longitudinal axis of the helix is perpendicular to the page. Starting with the N-terminal, successive amino acid residues (represented by circles) are distributed in the radial direction around the perimeter of a circle in 100 ° intervals. Thus, the amino acid residue n + l is placed 100 ° of the residue n, the residue n + 2 is located 100 ° of the residue n + l, and so on. The 100 ° placement represents the 3.6 amino acid residues per turn that are usually observed in an idealized helix. In FIGURE A, the hydrophobic and hydrophobic faces of the propeller are clearly visible; the hydrophilic amino acids are represented as light circles, and the hydrophobic amino acid residues are represented as shaded circles. FIGURE IB represents a helical network diagram of the idealized antipathetic helix of Figure IA. (Lim, 1978, FEBS Lett. 89: 10-14). In a common helical network diagram, the helix is presented as a cylinder that has been cut along the center of its hydrophilic face and flattened. Thus, the center of the hydrophobic face, determined by the hydrophobic moment of the helix (Eisenberg et al., 1982, Nature 299: 371-374), is in the center of the figure and is oriented to exit the plane of the page. An illustration of the helical cylinder before being cut and flattened is shown in FIGURE 1C. By cutting the cylinder along the different planes, it is possible to observe different views of the same antipathic helix, and different information about the properties of the helix is obtained. The unfriendly nature of the a helix formed by the core peptides of the structure (I) in the presence of lipids is illustrated in FIGURE 2. FIGURE 2A presents a diagram of the Schiffer-Edmundson helical wheel, FIGURE 2B represents a diagram of helical network illustrating the hydrophobic face and FIGURE 2C presents a helical network diagram illustrating the hydrophilic side. In each of FIGURES "2A, 2B and 2C, the hydrophilic residues are represented as clear circles, the hydrophobic residues as shaded circles, and residues that may be hydrophilic or hydrophobic with partially shaded circles, as will be described in more detail below. together with altered or mutated forms of the peptides of structure (I), certain amino acid residues can be substituted with other amino acid residues so that the hydrophilic and hydrophobic faces of the helix formed by the peptides can not be completely composed of amino acids Thus, it should be understood that when referring to the antipathic helix formed by the core peptides of the invention, the phrase "hydrophilic face" refers to one face of the helix having a total net hydrophilic character. phrase "hydrophobic face" refers to a face of the peptide having hydrophobic character or "total net." The phrase "hydrophilic face" refers to a face of the peptide having a net hydrophobic character, in general. Although no specific theory is intended, it is considered that certain structural and / or physical properties of the antipathetic helix formed by the core peptides of structure (I) are important for the activity. These properties include the degree of amphipathicity, general hydrophobicity, average hydrophobicity, hydrophobic and hydrophilic angles, hydrophobic moment, average hydrophobic moment and net charge of the helix a. Although the worm wheel diagrams in FIGURE 2A provide a convenient means to visualize the antipathetic nature of structure core peptides (I), the degree of amphipathicity (degree of asymmetry of hydrophobicity) can be conveniently quantified by calculating the hydrophobic moment (μp) of the helix. Methods for calculating μH for a specific peptide sequence are well known in the art, and are described, for example, in Eisenberg, 1984, Ann. Rev. Biochem. 53: 595-623. The actual μ obtained for a specific peptide will depend on the total number of amino acid residues that make up the peptide. Thus, it is generally not informative to directly compare μH for peptides of different lengths. The amphipathicities of the peptides of different lengths can be directly compared by means of the average hydrophobic moment (< μH) the average hydrophobic moment can be obtained by dividing μp by the number of residues in the helix (ie, between < μp = UH / N) • In general, core peptides that exhibit an < μ? in the range of 0.45 to 0.65, determined using the normalized consensus hydrophobicity scale of Eisenberg (Eisenberg 1984, J. Mol. Biol. 179: 125-142) are considered within the scope of the present invention, with an < μj_ in the range of 0.50 to 0.60 being preferred.

The general or total hydrophobicity (H0) of a peptide can be conveniently calculated by taking the algebraic sum of the hydrophobicities of each amino acid residue in the peptide (ie, N Ho =? H i = i where N is the number of amino acid residues in the peptide, and Hx is the hydrophobicity of the i th amino acid residue). The average hydrophobicity (< H0 >) is the hydrophobicity divided by the number of amino acid residues (ie, <μ0> = HQ / N). In general, core peptides exhibiting an average hydrophobicity in the range of -0.050 to -0.070, determined using the Eisenberg standardized consensus hydrophobicity scale (Eisenberg, 1984, J. Mol. Biol. 179: 125-142) are considered to be within the scope of the present invention, with an average hydrophobicity in the range of -0.30 to -0.055 being preferred. The total hydrophobicity of the hydrophobic face (H0P °) of an antipathic helix can be obtained by taking the sum of the hydrophobicities of the hydrophobic amino acid residues that enter the hydrophobic angle as defined below (ie, N H0 h0 = S Hi i = i, where E ± is as defined above and NH is the total number of hydrophobic amino acids on the hydrophobic face). The average hydrophobicity of the hydrophobic face (< H0ph ° >) is H0ph ° / NH, where NH is as defined above. In general, the core peptides that exhibit an < HoP ° > in the range of 0.90 to 1.20, determined using the Eisenberg consensus hydrophobicity scale (Esisenberg, 1984, supra, Eisenberg et al., 1982, supra) are considered to be within the scope of the present invention, with < HQP ° > in the range of 0.94 to 1.10. The hydrophobic angle (pho angle) is generally defined as the angle or arc covered by the longest continuous extension of the hydrophobic amino acid residues when the peptide is arranged in the representation of the Schiffer-Edmundson helical wheel (ie, the number of contiguous hydrophobic residues on the wheel multiplied by 20 °). The hydrophilic angle (angle phi) is the difference between 360 ° and the angle pho (that is, 360 ° - angle pho). Those skilled in the art will recognize that the angles pho and phi will depend, in part, on the number of amino acid residues in the peptide. For example, with reference to FIGS. 5A and 5B, it can be seen that only 18 amino acids are adjusted around a rotation of the Schiffer-Edmundson helical wheel. Few amino acids leave a hole in the wheel; more amino acids cause certain positions of the wheel that will be occupied by more than one amino acid residue. In the case of peptides containing more than 18 amino acid residues, such as core peptides of structure (I), a "continuous" extension of hydrophobic amino acid residues is understood to mean that at least one amino acid residue at positions along the wheel occupied by 2 or more amino acids is a hydrophobic amino acid. Thus, with reference to FIGURE 5B, the angle pho is the arc covered by the residues 5, 16, 9, 2, 13, 6, 17, 10, 3 and 14 despite the presence of the hydrophilic residue at position 20, as the residue in position 2, which occupies the same position in the wheel as residue 20, is a hydrophobic residue. Typically, core peptides having a pho angle in the range of 160 ° to 220 ° are considered within the scope of the invention, with a pho angle in the range of 180 ° to 200 ° being preferred. Certain structural and / or physical characteristics of the core peptides of structure (I) are illustrated in FIGURES 3 and 4. FIGURE 3B presents a helical network diagram of an exemplary core peptide of the invention, peptide 146 (PVLELFENLLERLLDALQKKLK; SEQ ID NO: 146), illustrating the distribution of the charge along the hydrophilic face of the helix. In FIGURE 3B, the helical cylinder has been cut along the center of the hydrophobic and flattened face. The three Leu (L) hydrophobic residues that replace the hydrophilic residues in the 22-th Segrest consensus (FIGURE 3A) are shared. As can be seen in FIGURE 3B, the positively charged amino acid residues are grouped in the last C-terminal turn of the helix (the C-terminal is at the top of the page). Although it is not intended to adhere to any specific theory, it is considered that this group of basic residues in the C-terminal (residues 19, 20 and 22) stabilizes the helix through electrostatic charge (NH3) -dipolo interactions of the helix. Stabilization is also considered to occur through the hydrophobic interactions between lysine side chains and the helix nucleus (see, Groebke et al., 1996, Proc Nati Acad Sci USA 93: 4025-4029; Esposito et al., 1997, Biopolymers 41: 27-35). With the exception of the positively charged C-terminal group, the negative charges are distributed on the rest of the hydrophilic side, with at least one amino acid residue negatively charged (acid) per turn, giving rise to a continuous spread of negative charges as length of the hydrophilic face of the propeller. A positive charge is located at residue 12, which potentially contributes to the stability of the propeller by forming a salt bridge with an acid residue a turn away from the helix. FIGURE 4B depicts a helical network diagram illustrating the hydrophobic face of the antipathetic helix formed by the exemplary core peptide 146 (SEQ ID NO: 146). In FIGURE 4B, the helical cylinder is cut along the center of the hydrophilic face and is flattened. The hydrophobic face of the core peptide consists of two hydrophobic residues per turn, except for the last C-terminal turn, where the basic residues dominate. NMR studies indicate that amino acid residues 3, 6, 9, and 10 of this core peptide form a hydrophobic cluster near the N-terminus of the helix. Phe-6 is centered in this group and is considered to have an important function in the stabilization of the hydrophobic group. Although it is not intended to adhere to any specific theory, it is considered that the hydrophobic group formed by residues 3, 6, 9 and 10 is significant effecting the binding to lipids and the activation of the LCAT. It is expected that the antipathetic peptides bind to the phospholipids by pointing their hydrophobic faces towards the alkyl chains of the lipid moieties. Thus, it is considered that this highly hydrophobic group contributes to the strong lipid affinities observed by the core peptides of the invention. Since binding to lipids is a prerequisite for the activation of LCAT, it is considered that this hydrophobic group is also essential for the activation of LCAT. It is often found that aromatic residues are important in anchoring peptides and proteins to lipids (De Kruijff, 1990, Biosci, Rep. 10: 127-130, O'Neil and De Grado, 1990, Science 250: 645- 651; Blondelle et al., 1993, Biochim Biophys, Acta 1202: 331-336). Thus, it is also considered that Phe-6, which is located in the center of the hydrophobic group, can also act in the anchoring of the core peptides of the structure (I) to the lipids. Interactions between core peptides of the invention and lipids give rise to the formation of the peptide / lipid complexes. As illustrated in FIGURE 10A, the type of complex obtained (cobalts, disks, vesicles or multilayers) depends on the molar lipid: peptide ratio, with comicelas generally being formed at molar lipid: low peptide and discoidal and vesicular molar ratios or of multiple layers being formed with molar lipid: peptide increasing ratios. This characteristic has been described for unfriendly peptides (Epand, The Amphipathic Helix, 1993) and for ApoA-I (Jones, 1992, Structure and Function of Apoliproteins, chapter 8, page 217-250). The molar lipid: peptide ratio also determines the size and composition of the complexes (see section 5.3.1, infra). The longitudinal axis of the a helix formed by core peptides of structure (I) has a general curved shape. In common antipathic helices, it has been found that the lengths of the hydrogen bonds of the hydrophilic and hydrophobic faces varies so that the hydrophobic side of the helix is concave (Barlow and Thornton, 1988, J. Mol. Biol. 201: 601 -619; Zhou et al., 1992, J. Am. Chem. Soc. 33: 11174-11183; Gesell et al., 1997, J. Biomol. NMR 9: 127-135). Although it is not intended to be attached to the theory, it is considered that the total curvature of the hydrophobic face of the helix may be important in joining the discoidal complexes, a curved helix allows the fr peptide to "fit" better to the edges of the discoidal particles, thereby increasing the stability of the peptide / disk complex. In the generally accepted structural model of ApoA-I, the antipathic helices are packed around the edge of the discoidal HDL (see, FIGURE 10B). In this The model assumes that the helices are aligned with their hydrophobic faces pointed towards the acyl chains of the lipid (Brasseur et al., 1990, Biochim, Biophys, Acta 1043: 245-252). The helices are arranged in an antiparallel mode, and a cooperative effect between The helices contribute to the stability of the discoidal HDL complex (Brasseur et al, supra). It has been proposed that a factor that contributes to the stability of the discoidal HDL complex is the existence of ionic interactions between acidic and basic residues, giving rise to the formation of intermolecular saline bridges or hydrogen bonds between residues in adjacent antiparallel helices, in this model, the peptides are considered not as a single entity, but as an interaction with at least two other adjacent peptide molecules (FIGURE 10B). It is also generally accepted that intramolecular hydrogen bonding or formation of the salt bridge between acidic and basic residues, respectively, at positions i and i + 3 of the helix stabilize the helical structure (Marqusee et al., 1985, Proc. Nati. Acad. Sci. USA 84 (24): 8898-8902). Thus, the additional key features of the core peptides of structure (I) are their ability to form intermolecular hydrogen bonds with each other when they are aligned in an antiparallel mode with their hydrophobic faces pointing in the same direction, as would be the case when the peptides they are bound to lipids (ie, / between the acid residues at positions 4 and 7 and the basic residues at positions 19, 20 and 22), and also their ability to form intramolecular hydrogen bonds or salt bridges near the N and C terminal of the propeller. The ability of the core peptides of structure (I) to form intermolecular hydrogen bonds is illustrated in FIGURE 6. In FIGURE 6, two exemplary core peptide 146 helices (SEQ ID NO: 146) are aligned in one mode antiparallel with their respective hydrophobic faces pointing in the same direction (out of the plane of the page). Interactions of H-bonds can occur between residues E-7 and Q-18 (Huyghues-Despointes et al., 1995, Biochemistry 34 (41): 13267-13271).

Also, when they are arranged in this antiparallel mode, the propellers are tightly packed; there is no steric hindrance avoiding close contact between the helices. Alterations in the sequence of the core peptides that affect the packaging of the helices negatively influence the activity of the core peptides. Thus, although it is not intended to adhere to any particular theory, it is considered that the ability of the core peptides of structure (I) to tightly pack and interact ionically to form saline bridges and / or intra- and / or intermolecular hydrogen bonds when binds lipids in an antiparallel mode is an important feature of the core peptides of the invention. The ability of core peptides to form favorable intermolecular peptide-peptide interactions is also considered relevant in the absence of lipids.

The core peptides of the invention self-associate, due in part to their < μH < Ho > and elevated hydrophobic angle (see, TABLE I, infra). The phenomenon of self-association depends on the pH conditions, the concentration of the peptide and the ionic strength and can give rise to several association states, from the monomeric forms to some multimeric forms (FIGURE 10A). The hydrophobic nucleus of the peptide aggregates favors the hydrophobic interactions with lipids. The ability of lipids to aggregate even at very low concentrations may favor their binding to lipids. Peptide-peptide interactions are also thought to occur in the nucleus of peptide aggregates and may compete with lipid-peptide interactions. In addition to the properties described above, it is considered that other parameters are important for the activity as well, including the total number of hydrophobic residues, the total number of residues with charge and the net charge of the peptides. A summary of the preferred physical and structural properties of the core peptides of structure (I) is given in TABLE I, below: TABLE I PHYSICAL PROPERTIES OF THE PREFERRED AGONISTS OF ApoA-I OF STRUCTURE (I) INTERVALO PROPERTY PREFERRED INTERVAL % hydrophobic amino acids 40 70 50 60 < H0 > • 0.050 to -0.070 -0.030 to -0.055 pho < H, > 0.90 - 1.2 0.94 - 1.1 < μH > 0.45 - 0.65 0.50 - 0.60 Angle pho 160 ° - 220 ° 180 ° - 200 ° # amino acids with 3 - 5 4 positive charge # amino acids with negative charge Net charge -1 to +1 Clustering Positions 3, 6, 9, 10 are hydrophobic hydrophobic amino acids Clustering acid at least one acidic amino acid per turn except for the last five amino acids C terminals Basic grouping at least three basic amino acids in the last five C terminal amino acids The properties of the amplicic helices formed by the core peptides of the invention differ significantly from the properties of the helices to amphipathic class A, particularly the helix to class A of the 22-th Segrest consensus. These differences are illustrated with the exemplary core peptide 146 (SEQ ID NO: 146) in FIGURES 3-5. With reference to FIGS. 4A and 4B, it can be seen that the hydrophobic face of peptide 146 has much greater hydrophobic character than the hydrophobic face of the 22-mer Segrest consensus. In particular, residue 5, 9 and 13 (shaded region of FIGURE 4B) are hydrophobic residues Leu (L) in peptide 146 (SEQ ID NO: 146) compared to residues loaded in the 22-mer consensus ( SEQ ID NO: 75). The substitution of these three residues with charge in the 22-mer Segrest consensus with Leu (L) hydrophobic residues gives rise to important differences in amphipathicity, hydrophobicity, pho angle and other properties of the helix.

A comparison of the physical and structural properties of peptide 146 (SEQ ID NO: 146) and 22-mer Segrest consensus (SEQ ID NO: 75) is given in TABLE II, below.

TABLE II COMPARISON OF THE PROPERTIES OF THE NUCLEUS PEPTIDES EXAMPLES 146 (SEQ ID NO: 146) WITH THE 22-MERO SEGREST CONSENSUS (SEQ ID NO: 75) PROPERTY CONSENSUS Peptide 146. 22-MERO # amino acids 22 22 # amino acids 13 10 hydrophilic # amino acids 9 12 hydrophobic% amino acid 41 55 hydrophobic < H0 > -0.293 -0.013 < H0ph ° > 0.960 0.990 < μH > 0.425 0.547 pho angle 100 ° 200 ° # amino acids with 5 4 positive charge # amino acids with 6 4 negative charge Net charge -1 0 It is important to note that the core peptides of structure (I) are composed of a larger percentage of hydrophobic residues, have a < Ho > and < μH ^ significantly higher, and have the pho angle larger than that of the 22-segrest consensus consensus (see FIGURES 5A and 5B). These differences in properties give rise to significant differences in activity. While the 22-th Segrest consensus (SEQ ID NO: 75) only presents 10% activation of the LCAT compared to native ApoA-I in the assays described herein, the peptides 146 (SEQ ID NO: 146) present 86% activation compared to native ApoA-I in the same assays. Peptide 144 (pVLELFENLLERLLDALQKKLK; SEQ ID NO: 144) which differs from peptide 146 (SED ID NO: 146) only by a D-Pro (p) in position Xi, presents 111% activation of the LCAT compared to native ApoA-I in the same assays. Certain amino acid residues in the core peptides of structure (I) can be substituted with other amino acid residues without significantly impairing, and in many cases still improving, the activity of the peptides. Thus, also contemplated by the present invention are the altered or mutated forms of the core peptides of structure (I), wherein at least one amino acid residue defined in the structure is substituted with another amino acid residue. Since one of the critical characteristics that affect the activity of the core peptides of the invention is its ability to form helices a in the presence of lipids having amphipathic properties and other properties described in the foregoing, it will be recognized that in the preferred embodiments of In the invention, the amino acid substitutions are conservative, ie, the amino acid residue that it replaces has physical and chemical properties that are similar to the amino acid residue being substituted. For purposes of determining conservative amino acid substitutions, amino acids can be conveniently classified into two main categories: hydrophilic and hydrophobic, depending primarily on the physical and chemical characteristics of the amino acid side chain. These two main categories can also be classified into subcategories that define with greater distinction the characteristics of the amino acid side chains. For example, the class of hydrophilic amino acids can further be subdivided into acidic, basic and polar amino acids. The class of hydrophobic amino acids can further be subdivided into apolar and aromatic amino acids. The definitions of the different categories of amino acids that define structure (I), (II) and (III) are as follows: "Hydrophilic amino acid" refers to an amino acid that has a hydrophobicity less than zero according to the hydrophobicity scale standardized consensus of Eisenberg, 1984, J. Mol. Biol., 179: 125-142. The hydrophilic amino acids genetically encoded Thr (T), Ser (S), His (H), Glu (E); Asn (N); Gln (Q), Asp (D); Lys (K) and Arg (R).

(- "Acid amino acid" refers to an amino acid hydrophilic having a pK value in the side chain of less than 7. Acid amino acids usually have negatively charged side chains at physiological pH due to the loss of a hydrogen ion. Genetically encoded acidic amino acids include Glu (E) and Asp (D). "Basic amino acid" refers to a hydrophilic amino acid having a pK value in the side chain greater than 7. Basic amino acids usually have positively charged side chains at physiological pH due to association with the hydronium ion. The basic amino acids genetically encoded include His (H), Arg (R) and Lys (K) "Polar amino acid" refers to a hydrophilic amino acid having a side chain that has no charge at physiological pH, but which has at least one bond in which the pair of electrons shared in common by two atoms is held more closely in one of the atoms. The genetically encoded polar amino acids include Asn (N), Gln (Q), Ser (S) and Thr (T). "Hydrophobic amino acid" refers to an amino acid having a hydrophobicity greater than zero according to the hydrophobicity scale in consensus of Eisenberg, 1984, J.

Mol. Biol., 179: 125-142. Genetically encoded hydrophobic amino acids include Por (P), He (I), Phe (F), Val (V), Leu (L), Trp (W), Met (M), Wing (A), Gly (G) and Tyr (Y). "Aromatic amino acid" refers to a hydrophobic amino acid with a side chain having at least one aromatic or heteroaromatic ring. The aromatic or heteroaromatic ring may contain one or more substituents such as -OH, -SH, -CN, -F, -Cl, -Br, -I, -N02, -NO, -NH2, -NHR, -NRR, -C (0) R, -C (0) OH, -C (0) NH2, -C (0 ) NHR, -C (0) NRR and the like, wherein each R is independently C? ~C6 alkyl, substituted Ci-Cd alkyl, Ci-Ce alkenyl, substituted Ci-C al alkenyl, C? ~C alqu alkynyl , Ci-Cß substituted alkynyl, Cs-C20 aryl substituted C5-C20 aryl, C6-C26 alkaryl substituted C6-C26 alkaryl, 5- to 20-membered heteroaryl or 5- to 20-membered heteroaryl, substituted, alkylated 6-26 membered heteroaryl or 6-26 membered heteroaryl, substituted. The genetically encoded aromatic amino acids include Phe (F), Tyr (Y) and Trp (W). "Non-polar amino acid" refers to a hydrophobic amino acid having a side chain that has no charge at physiological pH and that has junctions in which the pair of electrons shared in common by two atoms is generally maintained equally for each of the two atoms (that is, the side chain is not polar). The genetically encoded apolar amino acids include Leu (L), Val (V), He (I), Met (M), Gly (G) and Ala (A). "Aliphatic amino acid" refers to a hydrophobic amino acid having an aliphatic hydrocarbon side chain. Genetically encoded aliphatic amino acids include Ala (A), Val (V), Leu (L) and He (I). The amino acid residue Cys (C) is not common in that it can form disulfide bridges with other Cys residues (C) or other amino acids containing sulfanil. The capacity / residues of Cys (C) (and other amino acids with side chains containing -SH) to exist in a peptide in the form -SH, free, reduced, or in an oxidized disulfide bridge affects either the Cys residues (C) contributes to the net hydrophobic or hydrophilic character for a peptide. Although Cys (C) has a hydrophobicity of 0.29 according to the Eisenberg standardized consensus scale (Eisenberg, 1984, supra), it should be understood that for purposes of the present invention Cys (C) is classified as a hydrophilic, polar amino acid, notwithstanding the general classifications defined above. As will be appreciated by those skilled in the art, the categories defined above are not mutually exclusive. In this way, amino acids having side chains that have two or more physical chemical properties can be included in multiple categories. For example, the side chains of amino acids having aromatic portions that are further substituted with polar substituents, such as Tyr (Y), may have hydrophobic, aromatic and polar or hydrophilic properties, and may therefore be included in the aromatic categories and polar. The proper categorization of any amino acid will be apparent to those skilled in the art, especially in light of the detailed description that is provided herein. Certain amino acid residues, known as "helical breaker" amino acids, have a tendency to break down the structure of the helixes when they are contained in internal positions within the helix. Amino acid residues that exhibit helical cleavage properties are well known in the art (see, for example, Chou and Fasman, Ann.Rev. Biochem. 47: 251-276) and include Pro (P), Gly (G) and potentially all D-amino acids (when they are contained in an L-peptide, on the contrary, the L-amino acids break the helical structure when they are contained in a D-peptide.) Although these helix-breaking amino acid residues fall within the previously defined categories, with the exception of Gly (G) (described below), these residues should not be used to replace amino acid residues in internal positions within the helix, these should only be used to replace 1-3 amino acid residues in N-terminal and / or C-terminus of the peptide While the categories defined above have been exemplified in terms of genetically encoded amino acids, amino acid substitutions need not be, and in certain preferred modalities they are not restricted to genetically encoded amino acids. Actually, many of the preferred structure peptides (I) contain genetically uncoded amino acids. Thus, in addition to the genetically encoded amino acids that occur in nature, the amino acid residues in the core peptides of structure (I) may be substituted with uncoded, natural amino acids and synthetic amino acids. Certain common amino acids that provide useful substitutions for the core peptides of structure (I) include, but are not limited to, β-alanine (β-Ala) and other omega amino acids such as 3-aminopropionic acid, 2,3-diaminopropionic acid (Dpr). ), 4-aminobutyric acid and so on; a-aminoisobutyric acid (Aib); e-aminohexanoic acid (Aha); d-aminovaleric (Ava); N-methylglycine or sarcosine (MeGly); Ornithine (Orn); citrulline (Cit); t-butylalanine (t-BuA); t-butylglycine (t-BuG); N-methyl isoleucine (Melle); phenylglycine (Phg); cyclohexylalanine (Cha); norleucine (Nle); naphthylalanine (Nal); 4-chlorophenylalanine (Phe (4-Cl)); 2-fluorophenylalanine '»(Phe-2-F)); 3-fluorophenylalanine (Phe-3-F)); 4-5 fluorophenylalanine (Phe (4-F)); phenylcilamine (Pen); acid 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid (Tic); β-2- thienylalanine (Thi); methionine sulfoxide (MSO); homoarginine (hArg); N-acetyl lysine (AcLys); 2, 4-diaminobutyric acid (Dbu); 2, 3-diaminobutyric acid (Dab); p-aminophenylalanine (Phe (pNH2)); N-methyl valine (MeVal); homocysteine (hCys), homophenylalanine (hPhe) and homoserin (hSer); hydroxyproline (Hyp), homoproline (hPro), N-methylated amino acids and peptoids (N-substituted glycines). Classifications of amino acids genetically encoded and uncoded, common according to the categories defined above are summarized in TABLE III, below. It should be understood that TABLE III is for illustrative purposes only and is not intended to be an exhaustive list of amino acid residues that can be be used to replace the core peptides described herein. Other amino acid residues not specifically mentioned herein can easily be classified on the basis of their physical and chemical properties observed in light of the definitions given. provide in the present. _ • TABLE III CLASSIFICATIONS OF COMMON AMINO ACIDS Classification Genetically Non-genetically encoded Hydrophobic Php, Nal, Thi, Tic, Phe (4- Aromatic F, Y, W Cl), Phe (2-F), Phe (3-F), Phe, (4-F), hPhe t-BuA, t-BuG, MelLe, Nle, .Apolar L, V, I, M, G, A, P MeVal, Cha, McGly, Aib b-Wing, Dpr, Aib, Aha, MeGly, t-BuA, t-BuG, Aliphatic A, V, L, I Melle, Cha, Nle, MeVal Hydrophilic Acid D, Basic E H, K, R Dpr, Orn, hArg, Phe (p-NH2), Dbu, Polar Dab C, Q, N, S, T Cit, AcLys, MSO, bALa, hSer With cleavage of P # G D-Pro and other amino acid helix (in L-peptides) Although in many cases, the amino acids of the core peptides of structure (I) will be substituted with L-enantiomeric amino acids, the substitutions are not limited to the L-enantiomeric amino acids. Thus, substitutions are also included in the definition of "mutated" or "altered" forms where at least one L-amino acid is substituted with an identical D-amino acid (eg, L-Arg-D-Arg) or with an D-amino acid of the same category or subcategory (for example, L-Arg-D-Lys), and vice versa. Indeed, in certain preferred embodiments that are suitable for oral administration to animal individuals, the peptides may be advantageously composed of at least one D-enantiomeric amino acid. Peptides containing these D-amino acids are considered more stable to degradation in the oral cavity, the intestine or in serum compared to peptides composed exclusively of L-amino acids. As noted in the above, D-amino acids tend to break the structure of helices a when they are contained in internal positions of an L-peptide to helical. In addition, it has been observed that certain mutated forms of the core peptides of structure (I) that are completely composed of D-amino acids exhibit significantly lower LCAT activation in the assay described herein as compared to identical peptides composed entirely of L-amino acids. As a consequence, the D-amino acids should not be used to replace internal L-amino acids; Substitutions with D-amino acids should not be limited to 1-3 amino acid residues at the N-terminus and / or C-terminus of the peptide. As described above, the amino acid Gly (G) generally acts as a helix-breaking residue when it is contained in internal positions of a peptide. Most surprisingly, applicants have discovered that while the helical structure of the core peptides of the invention breaks down in the absence of lipids when internal amino acid residues are substituted with Gly (G) in the presence of lipids such as Gly (G) containing Peptides present significant helical structure, as well as activity. For example, while peptide 154 (PVLELFENLLERGLDAQKKLK; SEQ ID NO: 154) presents only 13% helical structure in buffer solution, 76% helical structure was observed in the presence of micelles. Notably some kernels of pepids contained within Gly (G) present residues > 38% activation of the LCAT. Thus, although Gly (G) is generally considered a helix-breaking residue, Gly (G) can be used to substitute amino acids in internal positions of the core peptides of structure (I). Preferably, only the internal residues located within about ± 1 helical turn of the center of the peptide (particularly for peptides composed of an even number of amino acids) are substituted with Gly (G). Furthermore, it is preferred that only one internal amino acid residue in the peptide is substituted with Gly (G). Preferred embodiments of the ApoA-I agonists of the invention containing internal glycines are described in section 5.1.2, infra. Using the classifications of amino acid residues described above together with the presentations of the Schiffer-Edmundson helical wheel and the helical lattice diagram of the core peptides of structure (I), as well as the detailed description of the desired properties that are provided in present, the altered or mutated forms of the core peptides of structure (I) which substantially retain the amphipathic and other properties of the helix, and which are therefore considered within the scope of the present invention, can be easily obtained. In a preferred embodiment of the invention, the altered or mutated forms of the core peptides of structure (I) are obtained by fixing the hydrophilic or hydrophobic residues according to structure (I) and replacing at least one non-fixed residue with another amino acid, preferably conservatively, ie , with another amino acid of the same category or subcategory. The residues that make up the basic and / or hydrophobic groupings can also be fixed, according to the structure (I), and at least one non-fixed residue substituted, preferably conservatively. In another preferred embodiment, the altered or mutated forms of the core peptides of structure (I) are obtained by fixing the hydrophilic amino acid residues located within the hydrophilic face of the helix according to structure (I) and replacing at least one amino acid residue not fixed with another amino acid, preferably with another amino acid residue of the same category or subcategory. With reference to FIGURE 2A, it can be observed that residues 1, 4, 7, 8, 11, 12, 15, 18, 19 and 22 are located within the hydrophilic face of the antipathetic helix formed by the core peptides of structure (I) Of these residues, all are hydrophilic except residue 1, which can be hydrophilic or hydrophobic. Thus, in a preferred embodiment, the residues 4, 7, 8, 11, 12, 15, 18, 19 and 22 are fixed according to the structure (I) and at least one of the residues 1, 2, 3, 5 , 6, 9, 10, 13, 14, 16, 17, 20 and 21 is substituted with another amino acid of the same category, preferably with another amino acid of the same subcategory. Otherwise, residue 1 is also fixed according to structure (I) and at least one of residues 2, 3, 5, 6, 9, 10, 13, 14, 16, 17, 20 and 21 is replaced .

In a particularly preferred embodiment, the basic C-terminal grouping (residues 18, 19, 20 and 22) are also fixed according to structure (I), and only residues 2, 3, 5, 6, 9, 10, 13, 14, 16, 17 and / or 21 are replaced. In another particularly preferred embodiment, the hydrophobic group is also fixed, and only residues 2, 5, 13, 14, 16, 17, 20 and / or 21 are substituted. In still another, particularly preferred, embodiment, both basic and hydrophobic groups are fixed and residues 2, 3, 5, 13, 14, 16, 17, 20 and / or 21 are substituted.

In another preferred embodiment of the invention, the altered or mutated forms of the core peptides of the invention are obtained by fixing the hydrophobic amino acid residues located within the hydrophobic face of the helix and replacing at least one non-fixed amino acid residue with another amino acid residue, preferably with another residue of the same category or subcategory. With reference to FIGURE 2A, it can be seen that residues 2, 3, 5, 6, 9, 10, 13, 14, 16, 17, 20 and 21 are located within the hydrophobic face. Of these, all are hydrophobic minus the residue 20 which is hydrophilic. Thus, in a preferred embodiment, the residues 2, 3, 5, 6, 9, 10, 13, 14, 16, 17, and 21 are fixed according to the structure (I) and at least one of the residues 1, 4, 7, 8, 11, 12, 15, 18, 19, 20 and 22 is substituted with another amino acid residue, preferably with another amino acid of the same category or subcategory. In a particularly preferred embodiment, the basic C-terminal group is also fixed, and only residues 1, 4, 7, 8, 11, 12 and / or 15 are substituted. In another embodiment, the altered or mutated forms of the peptides of structure (I) are obtained by fixing all residues amino acids residing within the hydrophobic or hydrophilic face of the helix and substituting, preferably in a conservative manner, at least one amino acid residue which it resides on the other side with another amino acid residue. The residues comprising the hydrophobic group and / or the basic group can also be optionally fixed according to structure (I), as defined above. In another embodiment of the invention, altered or mutated forms of structure (I) are obtained by replacing at least one amino acid with a non-conservative amino acid. Those skilled in the art will recognize that these substitutions should not substantially alter the amphipathic and / or structural properties of the described helix, supra. Thus, in certain cases it may be desirable to substitute one or more pairs of amino acids to preserve the net properties of the helix. Other guidelines for selecting suitable amino acid substitutions are provided by the sequences of the peptides listed in TABLE X (see, section 8.3, infra). In still another embodiment of the invention, from the first to the fourth amino acid residues at the N-terminal and / or C-terminal of the core peptides of structure (I) are substituted with one or more amino acid residues, or one more peptide segments, which they are known to confer stability to the regions of the helical secondary structure (residues or "cap" segments). These residues and cap segments are well known in the art (see, for example, Richardson and Richardson, 1988, Science 240: 1648-1652, Harper et al., 1993, Biochemistry 32 (30): 7605-7609; Dasgupta and Bell; , 1993, Int. J. Peptide Protein Res. 41: 499-511; Seale et al., 1994, Protein Science 3: 1741-1745; Doig et al., 1994, Biochemistry 33: 3396-3403; Zhou et al. , 1994, Proteins 18: 1-7, Doig and Baldwin, 1995, Protein Science 4: 1325-1336, Odaert et al., 1995, Biochemistry 34: 34: 12820-12829, Petrukhov et al., 1996, Biochemistry 35: 387-397; Doig et al., 1997, Protein Science 6: 147/155). Otherwise, from the first to the fourth N-terminal and / or C-terminal amino acid residues of structure (I) can be substituted with mimetic peptide portions that mimic the structure and / or properties of the residues or cap segments. Suitable cap mimetics are well known in the art, and are described, for example, in Richardon and Richardson 1988, Science 240: 1648-1652; Harper et al., 1993, Biochemistry 32 (30): 7605-7609; Dasgupta and Bell, 1993, Int. J. Peptide protein Res. 41: 499-511; Seale et al., 1994, Protein Science 3: 1741-1745; Doig et al., 1994, Biochemistry 33: 3396-3403; Zhou et al., 1994, Proteins 18: 1-7; Doig and Baldwin, 1995, Protein Science 4: 1325-1336; Odaert et al., 1995, Biochemistry 34: 34: 12820-12829; Petrukhov et al., 1996, Biochemistry 35: 387-397; Doig et al., 1997, Protein Science 6: 147-155). Although the structure (I) contains 22 specific amino acid residue positions, it should be understood that the core peptides of the invention may contain less than 22 amino acid residues. In fact, truncated or internally deleted forms of structure (I) containing less than 18 or even 15 amino acid residues that substantially retain the characteristics and general properties of the antipathetic helix formed by the core peptides of structure (I) are considered within the scope of the present invention. The truncated forms of the peptides of structure (I) are obtained by deletion of one or more amino acids of the N and / or C terminal structure (I). Forms with internal deletions of the structure (I) are obtained by deleting one or more amino acids from the internal positions within the peptide of structure (I). Amino acid residues with internal deletions may or may not be consecutive residues. Those skilled in the art will recognize that deletion of an internal amino acid residue from a core peptide of structure (I) will cause the plane of the hydrophilic / hydrophobic interface of the helix to rotate 100 ° at the point of deletion. As these rotations can significantly alter the antipathetic properties of the resulting helix, in a preferred embodiment of the invention the amino acid residues are subjected to deletion to substantially preserve the alignment of the hydrophilic-hydrophobic interface plane along the longitudinal axis of the propeller. This can be conveniently achieved by deleting a sufficient number of consecutive or non-consecutive amino acid residues so that deletion of a complete helical turn is made. An idealized helix contains 3.6 residues per turn. Thus, in a preferred embodiment, the deletion of groups of 3 to 4 consecutive or non-consecutive amino acid residues is performed. If the deletion of 3 amino acids or 4 amino acids is made, it will depend on the position within the helix of the first residue that is going to be subjected to deletion. The determination of the appropriate number of consecutive or non-consecutive amino acid residues constituting a complete helical turn from any particular starting point within an antipathic helix is within the capabilities of those skilled in the art. Due to the supposed importance of the basic group in the C-terminal of the core peptides of structure (I) in the stabilization of the helix, and the importance of the hydrophobic group in effecting the binding to lipids and the activation of the LCAT, in the Preferred embodiments of the invention, the residues comprising the basic and hydrophobic groups are not subject to deletion. Thus in the preferred embodiments, residues 18, 19, 20 and 22 (basic group) and residues 3, 6, 9, and 10 (hydrophobic group) are not subject to deletion. The core peptides of structure (I) may also be extended in one or both terms or internally with additional amino acid residues that do not substantially interfere with, and in some embodiments still improve, the structural and / or functional properties of the peptides. In fact, extended core peptides containing 23, 25, 26, 29 or even more amino acid residues are considered within the scope of the present invention. Preferably, these extended peptides will substantially retain the net amphipathicity and other properties of the peptides of structure (I). Of course, it will be recognized that the addition of amino acids internally will rotate the plane of the hydrophobic / hydrophilic interface at the point of insertion in a manner similar to that already described for internal deletions. Thus, the considerations described above in connection with internal deletions also apply to internal additions. In one embodiment, the core peptides are extended at the N and / or C terminal by a last helical turn. Preferably, these extensions will stabilize the helical secondary structure in the presence of lipids, such as the amino acids and cap segments described above. In a particularly preferred embodiment, the core peptide of structure (I) is extended at the C-terminus by a single basic amino acid residue, preferably Lys (K). When extended like this, Xi is preferably D-Pro (p) or Gly (G) X2 is preferably Val (V) X3 is preferably Leu (L) X4 preferably is Asp (D) X5 preferably is Leu (L) X preferably is Phe (F) X7 preferably is Arg (R) Xs preferably is Glu (E) Xg is preferably Leu (L) Xio preferably is Leu (L) Xn is preferably Asn (N) X12 preferably is Glu (E) X13 preferably is Leu (L ) Xi preferably is Leu (L) X3.5 preferably is Glu (E) Xi6 preferably is Ala (A) X17 preferably is Leu (L); X18 is preferably Lys (K); X19 preferably is Gln (Q); X20 is preferably Lys (K); X2? preferably it is Leu (L); and / or Xi8 is preferably Lys (K). Also included within the scope of the present invention are the "blocked" forms of the agonists of ApoA-I, that is, the forms of ApoA-I agonists in which the N and / or C terminal is blocked with a portion capable of reacting with -NH2, N-terminal or -C (0) OH, C-terminal. It has been found that by removing the N and / or terminal C charges of the ApoA-I agonists of the invention containing 18 or less amino acid residues (by synthesis of the N-acetylated peptides / ester / hydrazides / alcohols of the N-acetylated peptide the same) the approximating agonists are produced, and in some modalities still exceed, the activity of the unblocked form of the agonist.

In some embodiments containing 22 or more amino acids, blocking of the N or C terminal produces ApoA-I agonists that exhibit less activity compared to non-blocked forms. However, the terminal N and C block of ApoA-I agonists composed of 22 or more amino acids is expected to reestablish activity. Thus, in a preferred embodiment of the invention, the N and / or C-terminal (preferably both terminals) of the core peptides containing 18 or fewer amino acids are blocked, while the N and C terminals of the peptides contain 22 or more amino acids. They are blocked or not blocked. Common N-terminal blocking groups include RC (O) -, where R is -H, Ci-Cß alkyl, Ci-Cβ alkenyl, Ci-Cβ alkynyl. C5-C20 aryl > C6-C26 alkaryl / 5-20 membered heteroaryl or 6-26 membered heteroaryl. N-terminal blocking groups include acetyl, formyl and dansyl. Common terminal C-blocking groups include -C (0) NRR and -C (0) OR, where each R is independently defined as above. Preferred C-terminal blocking groups include those where each R is independently methyl. Although without attempting to adhere to any specific theory, terminal blocking groups are considered to stabilize helix a in the presence of lipids (see, eg, Venkatachelapathi et al., 1993, PROTEINS: Structure, Function and Genetics, 15: 349- 359). The native structure of ApoA-I contains eight helical units which are considered to act to bind lipids (Nakagawa et al., 1985, J. Am. Chem. Soc. 107: 7087-7092; Anantharamaiah et al., 1985, J. Biol .. Chem. 260: 10248-10262; Vanloo et al., 1991, J. Lipid Res. 32: 1253-1264; Mendez et al., 1994, J. Clin. Invest. 94: 1698 -1705; Palgunari et al., 1996, Arterioscler, Thromb. Vasc. Biol. 16: 328-338; Demoor et al., 1996, Eur. J. Biochem. 239: 74-84). Thus, also included in the present invention are ApoA-I agonists composed of dimers, trimers, tetramers and even higher order polymers ("multimers") of the core peptides described herein. These multimers can be in the form of cascade repeats, branched networks or combinations of both. The core peptides can be directly linked together or separated by one or more linkers. The core peptides comprising the multimers may be the peptides of structure (I), analogs of the structure (I), mutated forms of the structure (I), truncated forms or with internal deletions of the structure (I), extended forms of the structure (I) and / or combinations thereof. Core peptides can be connected in a head-to-tail mode (ie, N terminal to C terminal), in a head-to-head mode (ie, N terminal to N terminal), in a queue to queue mode (ie, C terminal to C terminal), or combinations thereof. In one embodiment of the invention, the multimers are cascade repeats of two, three, four and up to about 10 core peptides. Preferably, the multimers are cascade repeats from two to eight core peptides. Thus, in one embodiment, the ApoA-I agonists of the invention comprise multimers having the following structural formula: (II) HH- [LLm-HH] n-LLm-HH wherein: each m is independently an integer from 0 to 1, preferably 1; n is an integer from 0 to 10, preferably from 0 to 8; each "HH" independently represents a peptide core or peptide analog of structure (I) or a mutated, truncated, internally deleted or extended form thereof as described herein; each "LL" independently represents a linker; each "-" independently designates a covalent bond.

In structure (II), linker LL can be any bifunctional molecule capable of covalently binding two peptides together. Thus, suitable linkers are bifunctional molecules in which the functional groups can be covalently linked to the N and / or C-terminal of a peptide. Suitable functional groups for the N or C terminal binding of the peptides are well known in the art, since they are the proper chemistry to effect a covalent bond formation in this manner. The linker can be flexible, rigid or semi-rigid, depending on the desired properties of the multimer. Suitable linkers include, for example, amino acid residues such as Pro or Gly or peptide segments containing from about 2 to about 5, 10, 15 or 20 or even more amino acids, bifunctional organic compounds such as H2N (CH2) nC00H where n is an integer from 1 to 12, and the like. Examples of these linkers, as well as the methods for preparing these linkers and the peptides incorporating the linkers are well known in the art (see, for example, Hünig et al., 1974, Chem. Ver. 100: 3039-3044; Basak et al., 1994, Bioconjug Chem., 5 (4): 301-305). In a preferred embodiment of the invention, the cascade repeats are internally penetrated by a single proline residue. For this purpose, in those cases where the core peptides are finished in their N or C terminal with proline, as it can be, for example, where Xi in the structure (I) is Pro (P) or D-Pro (p), m in structure II is preferably 0. In these cases where the core peptides do not contain a proline in the N or C terminal, LL is preferably Pro (P) or D-Pro (p) and m preferably is 1. In certain embodiments of the invention, it may be desirable to employ linkers that can be dissociated and that allow the release of one or more helical segments (HH) under certain conditions. Suitable linkers that can be dissociated include peptides having amino acid sequences that are recognized by proteases, oligonucleotides that are dissociated by endonucleases and organic compounds that can be dissociated by chemical means, such as under acidic, basic or other conditions. Preferably, the dissociation conditions will be relatively moderate so as not to denature or otherwise degrade the helical segments and / or the non-dissociated linkers that make up the multimeric ApoA-I agonists. The peptide linkers and oligonucleotides that can be selectively dissociated, as well as the means for dissociating the linkers are well known and will be apparent to those skilled in the art. Suitable organic compound binders that can be selectively dissociated will be apparent to those skilled in the art, and include those described, for example, in WO94 / 08051, as well as the references mentioned therein. In a preferred embodiment, the linkers employed are peptides that are substrates for endogenous circulatory enzymes, thereby allowing the multimeric ApoA-I agonists to be selectively dissociated in vivo. Endogenous enzymes suitable for unfolding the linkers include, for example, proapolipoprotein A-I propeptidase. Suitable enzymes, as well as the peptide segments that act as substrates for these enzymes, are well known in the art (see, for example, Edelstein et al., 1983, J. Biol. Chem. 258: 11430-11433; Zanis, 1983, Proc. Nati, Acad. Sci. USA 80: 2575-2578). As already described, an important feature of the core peptides of the invention is their ability to form intermolecular hydrogen bonds or salt bridges when arranged in an antiparallel mode. Thus, in a preferred embodiment of the invention, linkers of sufficient length and flexibility are used to allow the helical segments (HH) of structure (II) to be aligned in an antiparallel fashion and form intermolecular hydrogen bonds or salt bridges in the presence of of lipids. Linkers of sufficient length and flexibility include, but are not limited to, Pro (P), Gly (G) Cys-Cys, H2N- (CH2) n-C00H, where n is from 1 to 12, preferably from 4 to 6; H2N-aryl-COOH and carbohydrates. Otherwise, as the native apolipoproteins permit cooperating linkage between aniparallelic helical segments, the peptide linkers correspond in primary sequence to the peptide segments that connect the adjacent helices of the native apolipoproteins, including, for example, ApoA- I, ApoA-II, ApoA-IV, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE and ApoJ can conveniently be used to bind the core peptides. These sequences are well known in the art (see, for example, Rosseneu et al., "Analysis of the Primary and of the Secondary Structure or the Apolipoproteins," in: Structure and Function of Lipoproteins, C. 6, 159-183, CRC Press, Inc., 1992). Other linkers that allow the formation of intermolecular hydrogen bonds or salt bridges between cascade repetitions of antiparallel helical segments include inverse turns of the peptide such as ß turns and γ turns, as well as organic molecules that mimic the structures of ß turns and / or the turns? of the peptide. In general, inverse turns are segments of peptides that reverse the direction of the polypeptide chain to allow a single polypeptide chain to adopt regions of antiparallel or a-helical antiparallel plate structure. The ß turns are usually composed of four amino acid residues and turns? they are generally composed of three amino acid residues. The conformations and sequences of multiple β-peptide turns have been well described in the art and include, by way of example and not as limitation, type I, type I ', type II, type II', type III, type III ', type IV, type V, type V, type Via, type VIb, type VII and type VIII (see, Richardson, 1981, Adv. Protein Chem. 34: 167-339; Rose et al., 1985, Adv. Protein Chem. 37 : 1-109; Wilmot et al., 1988, J. Mol. Biol. 203: 221-232; Sibanda et al., 1989, J.

Mol. Biol. 206-759-777; Tramontano et al., 1989, Proteins: Struct. Funct. Genet 6: 382-394). The specific conformations of the peptide turns - • short as the ß turns depend mainly on the 5 positions of certain amino acid residues in the turn (usually Gly, Asn or Pro). In general, the ß-type I rotation is compatible with any amino acid residue in positions 1 to 4 of the rotation, except that Pro can not be in position 3. Gly predominates in position 4 and Pro predominates in position 2 of the type I and type II turns. Asp, Asn, Ser and Cys residues are often found in position 1, where their side chains frequently bind to hydrogen in NH of residue 3. In type II turns, Gly and Asn are found with higher frequency in position 3, as these more easily adopt the required angles in the main chain. In theory, type I 'turns have Gly in positions 2 and 3, and type II turns' have Gly in position 2. Type III turns can generally have the most amino acid residues, but type III 'turns usually require Gly at positions 2 and 3. Vía and VIb type turns generally have a cis and Pro peptide bond as an internal residue. For a review of the different types and sequences of ß turns in proteins and peptides in the reader should refer to Wilmot et al., 1988, J. Mol.

Biol. 203: 221-232. The conformation and sequences of multiple turns? peptides have also been well described in the art (see, for example, Rose et al., 1985, Adv. Protein Chem. 37: 1-109; Wilmer-White et al., 1987, Trends Biochem. Sci. 12: 189-192; Wilmot et al., 1988, J. Mol. Biol. 203: 221-232; Sibanda et al., 1989, J. Mol. Biol. 206: 759-777; Tramontano et al., 1989, Proteins: Struct. Funct. Genet 6: 382-394). All these types of structures of the ß turns and turns? and its corresponding sequences, as well as the structures and sequences of the ß turns and turns? newly discovered peptides are specifically contemplated by the invention. Otherwise, the linker (LL) can consist of a molecule or organic portion that mimics the structure of a ß turn or turn? of the peptide. These mimetic ß and / or turn γ portions, as well as methods for synthesizing peptides containing these portions, are well known in the art, include, among others, those described in Giannis and Kolter, 1993 Angew. Chem. Intl. Ed. Eng. 32: 1244-1267; Kahn et al., 1988, J. Molecular Recognition 1: 75-79; and Kahan et al., 1987, Tetrahedron Lett. 28: 1623-1626. In yet another embodiment of the invention, the multimers are in the form of branched networks (see, for example, FIGURE 7). These networks are conveniently obtained through the use of multi-function link portions that allow more than two helical units to be joined to a single link portion. Thus, branched networks employ molecules having 3, or even more functional groups that are capable of covalent attachment to the N and / or C terminal of a peptide. Suitable linker portions, for example, amino acid residues having side chains carrying hydroxyl, sulfanyl, amino, carboxyl, amide and / or ester functionalities, such as, for example, Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q), Lys (K), Arg (R) Orn, Asp (D) and Glu (E); or other organic molecules containing such functional groups. The helical segments attached to a single link portion do not need to be joined by equal terms. In fact, in some embodiments the helical segments are attached to a single link portion to be arranged in an antiparallel mode, ie, some of the helices are linked by their N-terminals, others by their C-terminals. The helical segments may be attached directly to the binding portion, or may be separated from the binding portion by one more bifunctional linkers (LL), as already described. With reference to FIGS. 7A and 7B, it can be seen that a branched network can be described in terms of the number of "nodes" of which the network consists, where each multifunctional link portion constitutes a node. In FIGS. 7A and 7B, the helical segments (i.e., the core peptides of the invention) are illustrated as cylinders, and the multifunctional link portions (or nodes) as (•), where the number of lines leaving the circle indicates the "order" (or number of functional groups) of the multifunctional link portion. The number of nodes in the network will generally depend on the total desired number of helical segments, and will usually be from about 1 to 2. Of course, it will be appreciated that for a given number of desired helical segments, the networks having link portions Higher order will have fewer nodes. For example, with reference to FIGURES 7A and 7B, a tertiary network (i.e., a network having trinfunctional link portions) of 7 helical units has three nodes (FIGURE 7A) whereas a network of quaternary order (i.e. , a network having tetrafunctional link portions) of seven helical units has only two nodes (FIGURE 7B). The networks can be of uniform order, ie, networks in which all the nodes are, for example, trifunctional or tetrafunctional link portions, or they can be of mixed order, for example, networks in which the nodes are mixtures of, for example, trifunctional and tetrafunctional linkages. Of course, it must be understood that even in networks of uniform order the link portions do not need to be identical. A tertiary network can employ, for example, two, three, four or even more different trifunctional link portions. Like the linear multimers, the helical segments comprising the branched network can be, but need not be, identical. An example of a mixed order branched network is illustrated in FIGURE 7C. In FIGURE 7C, the helical segments (i.e., the core peptides of the invention) are illustrated as cylinders and the multifunctional link portions as circles (•), where the number of lines exiting the circle indicates "order" ( or the number of functional groups) of the multifunctional link portion. The lines connecting the helical segments represent bifunctional linkers LL, as described above. The helical segments comprising the branched networks can be cascade repeats of core peptides, as already described. In an illustrative embodiment, the branched networks of the invention are described by the formula: (III) X ~ Nya-X (ya-1) (Nyb-X (yb-1)) p wherein: each X is independently HH- (LLm-HH) nLLm-HH; each HH is independently a core peptide of structure (I) or an analogous or mutated form, truncated, with internal or extended deletion thereof as described herein; each LL is independently a bifunctional linker; each m is independently an integer from 0 to 1; each n is independently an integer from 0 to 8; Nya and Ny are each independently a multifunctional link portion where Ya and Yb represent the number of functional groups in Nya and Nyb, respectively; each ya or y is independently an integer from 3 to 8; p is an integer from 0 to 7; and each "-" independently designates a covalent bond.

In a preferred embodiment, the branched network consists of a "Lys-tree", that is, a network wherein the multifunctional link portion is one or more residues Lys (K) see for example, FIGURE 7D). In an illustrative embodiment, the branched "tree Lys" networks of the invention are described by the formulas: (IV) (V) wherein: each X is independently HH- (LLm-HH) nLLm-HH; each HH is independently a core peptide or a peptide analog of structure (I) or a mutated, truncated, or internally deleted or extended form thereof as described herein; each LL is independently a bifunctional linker; Each n is independently an integer from 0 to 8; Each m is independently an integer from 0 to 1; R1 is -OR or -NRR; and each R is independently -H, Ci-Cß alkyl, Ci-Cβ alkenyl. Ci-Cß alkynyl; C5-C20 aryl (C6-C26) alkaryl of 5 to 20 members or alkyl-heteroaryl of 6 to 26 members. . 1.1. ANALYSIS OF THE STRUCTURE AND FUNCTION The structure and function of the core peptides or peptide analogs of the invention, as well as of the "ApoA-I agonists composed of these core peptides, including the multimeric forms described in the above, can be tested. to select the active agonists or mimetics of ApoA-I For example, core peptides or peptide analogs can be tested for their ability to form a helices in the presence of lipids, to bind lipids, deform complexes with lipids, activate the LCAT , to favor cholesterol efflux, etc. Methods and assays for analyzing the structure and / or function of the peptides are well known in the art.Prefered methods are given in the working examples, infra. of circular dichroism (DC) and nuclear magnetic resonance (NMR) described in section 7, infra, can be used to analyze the structure of the peptides or peptide analogs, particularly the degree of helicity in the presence of lipids. The ability to bind lipids can be determined using the fluorescence spectroscopy assay described in section 7, infra. The ability of the peptides and / or peptide analogs to activate the LCAT can be easily determined using the activation of the LCATs described in section 8, infra. The in vitro and in vivo assays described in sections 9, 10 and 11 below can be used to evaluate the half-life, distribution, cholesterol effusion and effects on the RCT. In general, the core peptides and / or the peptide analogs according to the invention having the properties mentioned in TABLE IV below are considered as active.

TABLE IV PROPERTIES OF ACTIVE PEPTIDES Ri is molar ratio of the lipid: peptide. As illustrated in the working examples, infra, core peptides that exhibit a high degree of activation of LCAT (> 38%) generally possess significant helical structure in the presence of small, lipid, unilamellar (SUV) vesicles ( > 60% helical structure in the case of unblocked peptides containing 22 or more amino acid residues and blocked peptides containing 18 o / less amino acid residues;> 40% helical structure in the case of unblocked peptides containing 18 or fewer amino acids), and those peptides that show little or no activation of CLAT possess little helical structure. However, in certain cases, peptides that have significant helical structure in the presence of lipids do not effect significant LCAT [sic].

In the same way, while core peptides that exhibit significant LCAT activation usually bind to lipids, in certain cases peptides that exhibit lipid binding do not effect significant activation of LCAT. As a consequence, those skilled in the art will recognize that although the ability of the core peptides described herein to form a helices (in the presence of lipids) and to bind to lipids is crucial to activity, in many cases these properties may not be enough Thus, in a preferred embodiment, the core peptides of the invention are subjected to a series of scans to select core peptides that exhibit significant pharmacological activity. In a first step, a core peptide is detected for its ability to form a helix a in the presence of lipids using the CD assay described in section 7 infra. These peptides that are at least 40% helical (unblocked peptides containing 18 or less amino acids) or 60% helical (blocked peptides containing 22 or more amino acids) in the presence of lipids (at a concentration of approximately 5 μM and a molar lipid ratio) : peptide of about 30) are then detected for their ability to bind to lipids using the fluorescence assay described in section 7, infra. Of course, only these core peptides containing a Trp (W) or fluorescent Nal residue are detected for lipid binding by fluorescence. However, for peptides that do not contain fluorescent residues, binding to lipids is evident when helicity increases in the presence of lipids. Core peptides that exhibit lipid binding in the presence of SUV (0.5-10 μM peptide, lipid molar ratio: peptide in the range of 1 to 50) are then detected for pharmacological activity. Of course, the pharmacological activity detected will depend on the desired use for ApoA-I agonists. In a preferred embodiment, the core peptides are detected for their ability to activate LCAT, as the peptides that activate the LCAT are particularly useful in the methods described herein. Core peptides having at least about 38% activation of LCAT compared to human, native ApoA-I (when determined using the LCAT activation assay described in section (8, infra), are preferred, with core peptides having 50%, 60%, 70%, 80% or even 90% or more activation being particularly preferred. . 1.2. PREFERRED MODALITIES The ApoA-I agonists of the invention can also be defined by means of the preferred embodiments. In a preferred embodiment, the ApoA-I agonists are peptides of 22 amino acid residues according to structures (I), or the forms acylated at an N-terminal and / or amidated or esterified at a C-terminus thereof . In another preferred embodiment, ApoA-I agonists are peptides of 22 amino acid residues according to structure (I) or forms acylated at an N-terminus and / or knotted or esterified at a C-terminus thereof, in which: Xi is Pro (P), Gly (G), Ala (A), Asn (N) or D-Pro (p); X2 is Ala (A), Val (V) or Leu (L); X5 is Leu (L); X6 is Phe (F); Xn is Glu (E); X19 is Lys (K); X20 is Lys (K); and / or X22 is Lys (K), and each of X3, X, X7. Xs. 9. X10. X11 X13 X14 X15. Xi6 Xi7. Xiß and X21, as defined above, are as defined above for structure (I). Particularly preferred ApoA-I antagonists, according to this aspect of the invention, are those in which X2 is Val (V); and / or X? 8 is Gln (Q). In still another preferred embodiment, the ApoA-I agonists are peptides of 22 amino acid residues according to structure (I), or the forms acylated at the N-terminal and / or amidated or esterified at the C-terminus of the same, in which one of X? 0, X113 or X14 is Gly (G) and the others of XiO X13 and X14 are different from Gly (G). When X14 is Gly (G), X7 is preferably Glu (E). Particularly preferred ApoA-I agonists according to this aspect of the invention are selected from the group consisting of: peptide 148 PVLELFENLLERLGDALQKKLK (SEQ ID NO: 148) peptide 151 PVLELFENLGERLLDALQKKLK (SEQ ID NO: 151) peptide 154 PVLELFENLLERGLDALQKKLK (SEQ ID NO: 154) and the forms amidated or esterified in the C-terminal and / or acylated in the N-terminal thereof. The modalities containing internal residues of glycine can be easily synthesized in high yield by means of segment condensation, thereby providing significant advantages for large-scale production. The condensation of segments, that is, the joining together of small constituent peptide chains to form a larger peptide chain, has been used to prepare multiple biologically active peptides, including residues of 44 amino acids that mimic ApoA-I (see, for example, example, Nakagawa et al.,1985, J. Am. Chem. Soc. 107: 7087-7083; Nokihara et al., 1989, Peptides 1988: 166-168; Kneib-Cordonnier et al., 1990, Int. J. Pept. Protein Res. 35: 527-538), and is considered the most cost effective method for bulk synthesis with high yield of the core peptides of the invention. The advantages of segment condensation synthesis include the ability to condense preformed segments in the solution phase and the ease of purification of the final product. The drawbacks of the method include low coupling efficiency and yield in the condensation step and low solubility of certain peptide sequences. The efficiency of the coupling of the condensation step can be increased significantly by increasing the coupling time. In general, the increase in the time of copulation gives rise to a greater racemization of the product (Sieber et al., 1970, Helv. Chim. Acta 53: 2135-2150). However, since glycine lacks a chiral center, it does not undergo racemization (proline residues, due to steric hindrance, also suffer little or no racemization during prolonged copulation times). Thus, the modalities containing internal glycine residues can be synthesized in bulk in high yield by condensation of segments synthesizing the constituent segments that take advantage of the fact that the glycine residues do not undergo racemization. Thus, modalities containing internal glycine residues provide significant advantages in the synthesis for bulk preparation on a large scale. In still another preferred embodiment, the ApoA-I agonists are peptides of 22 amino acid residues according to structure (I), or the forms acylated at the N-terminal and / or amidated or esterified at the C-terminal of the same, in which each of X? _, X13 and X14 is different from Gly (G).

In yet another preferred embodiment, the agonists of ApoA-I are altered or mutated forms of the peptides according to structure (I), or the forms acylated at the N-terminal and / or amidated or esterified at the C-terminal thereof, in which: X4 is different from Asp (D); X5 is different from Phe (F); X6 is different from Trp (W); X7 is different from Leu (L) or Asp (D); X9 is different from Gly (G) or Trp (W); X? 2 is different from Lys (K); X13 is different from Trp (W); X14 is different from Trp (W); X15 is different from Glu (E); Xi6 is different from Trp (W) or Leu (L); and / or X17 is different from Trp (W). In yet another preferred embodiment, the ApoA-I agonists are peptides with 22 amino acid receptors according to structure (I), or the forms acylated at the N-terminal and / or amidated or esterified at the C-terminus thereof, in which, when X7 is Leu (L), Xi0 is Trp (W), Xi is different from Gly (G) and / or Xi4 is different from Gly (G). A particularly preferred peptide according to this aspect of the invention is peptide 155 (PVLELFLNLWERLLDALQKKLK; SEQ ID NO: 155).

In another preferred embodiment, the ApoA-I agonists are peptides with 22 amino acid receptors according to structure (I), or the forms acylated at the N-terminal and / or amidated or esterified at the C-terminus thereof, at the which at least one of X? _, X2_ or X22 is different from Orn. Most preferably, at least two of X? _, X2o and X22 are different from Orn. Most preferably, each of X? _, X2o and X22 is different from Orn. In yet another preferred embodiment, the ApoA-I agonists of the invention are selected from the group of peptides set forth below: peptide 144: PVLELFENLLERLLDALQKKLK (SEQ ID NO: 144) peptide 145: GVLELFENLLERLLDALQKKLK (SEQ ID NO: 145) peptide 146: PVLELFENLLERLLDALQKKLK (SEQ ID NO: 146) peptide 147: PVLELFENLLERLFDALQKKLK (SEQ ID NO: 147) peptide 148: PVLELFENLLERLGDALQKKLK (SEQ ID NO: 148) peptide 149: PVLELFENLWERLLDALQKKLK (SEQ ID NO: 149) peptide 150: PLLELFENLLERLLDALQKKLK (SEQ ID NO: 150) peptide 151: PVLELFENLGERLLDALQKKLK (SEQ ID NO: 151) peptide 152: PVFELFENLLERLLDALQKRLK (SEQ ID NO: 152) peptide 153: AVLELFENLLERLLDALQKKLK (SEQ ID NO: 153) peptide 154: PVLELFENLLERGLDALQKKLK (SEQ ID NO: 154) peptide 155: PVLELFLNLWERLLDALQKKLK (SEQ ID NO: 155) peptide 186: PVLELFEQLLERLLDALQKKLK (SEQ ID NO: 186) peptide 187: PVLELFENLLERLLDALNKKLK (SEQ ID NO: 187) peptide 188: PVLELFENLLDRLLDALQKKLK (SEQ ID NO: 188); peptide 189: DVLELFENLLERLLDALQKKLK (SEQ ID NO: 189); and the acylated forms in the N-terminal and / or the amidated or esterified forms in the C-terminal thereof. In yet another preferred embodiment, the ApoA-I agonists of the invention are selected from the group of peptides set forth below: peptide 144 PVLELFENLLERLLDALQKKLK (SEQ ID NO 144) peptide 145 GVLELFENLLERLLDALQKKLK (SEQ ID NO: 145) peptide 146 PVLELFENLLERLLDALQKKLK (SEQ ID NO 146) peptide 147 PVLELFENLLERLFDALQKKLK (SEQ ID NO: 147) peptide 148 PVLELFENLLERLGDALQKKLK (SEQ ID NO: 148) peptide 149 PVLELFENLWERLLDALQKKLK (SEQ ID NO: 149) peptide 150 PLLELFENLLERLLDALQKKLK (SEQ ID NO: 150) peptide 151 PVLELFENLGERLLDALQKKLK ( SEQ ID NO: 151) peptide 152 PVFELFENLLERLLDALQKKLK (SEQ ID NO: 152) peptide 153 AVLELFENLLERLLDALQKKLK (SEQ ID NO: 153) peptide 154 PVLELFENLLERGLDALQKKLK (SEQ ID NO: 154) peptide 155 PVLELFLNLWERLLDALQKKLK (SEQ ID NO: 155) and the acylated forms in the N-terminus and / or the amidated or esterified forms in the C-terminus thereof In yet another preferred embodiment, the agonists of ApoA-I are multimeric forms according to structures II, III and / or IV in which each HH is independently a peptide according to structure (I), or an acylated form at the N-terminal - and / or a amidated or esterified form in the C-terminal thereof, or any of the preferred peptides according to structure (I) described herein. In yet another preferred embodiment, the core peptides that make up the ApoA-I agonists are not any of the following peptides: peptide 75: PV DEFREK NEELEA KQKLK (SEQ ID NO: 75); peptide 94: PVLDEFREKLNEALEALKQKLK (SEQ ID NO: 94); peptide 109 PVLDEFREK NERLEA KQ LK (SEQ ID NO: 109) peptide 237 LDDLLQKWAEAFNQLLKK (SEQ ID NO: 237) peptide 238 EWLKAFYEKVLEKLKELF * (SEQ ID NO: 238) peptide 241 DWFKAFYDKVFEKFKEFF (SEQ ID NO: 241) peptide 242 GIKKFLGSIWKFIKAFVG (SEQ ID NO: 242) peptide 243 DWFKAFYDKVAEKFKEAF (SEQ ID NO: 243) peptide 244 DWLKAFYDKVAEKLKEAF (SEQ ID NO: 244) peptide 245 DWLKAFYDKVFEKFKEFF (SEQ ID NO: 245) peptide 246 EWLEAFYKKVLEKLKELF (SEQ ID NO: 246) peptide 247 DWFKAFYDKFFEKFKEFF (SEQ ID NO: 247) peptide 248 EWLKAFYEKVLEKLKELF. { SEQ ID NO-248) peptide 249 EWLKAEYEKVEEKLKELF * (SEQ ID NO: 249) peptide 250 EWLKAEYEKVLEKLKELF * (SEQ ID NO: 250) peptide 251 EWLKAFYKKVLEKLKELF * (SEQ ID NO: 251) In a final preferred embodiment, ApoA-I agonists are not any of the peptides mentioned in Table X (section 8.3, infra) presenting an LCAT activation activity of less than 38% compared to human, native ApoA-I. . 2 SYNTHESIS AND PURIFICATION OF ApoA-1 PEPTIDE AGONISTS The core peptides of the invention can be prepared using almost any known technique for the preparation of peptides. For example, peptides can be prepared using peptide synthesis in conventional step or solid phase solution, or recombinant DNA techniques. . 2.1 CHEMICAL SYNTHESIS Core peptides can be prepared using conventional solid-phase step-wise solution synthesis (see, for example, Chemical Approaches to the Synthesis of Peptides and Proteins, Williams et al., Eds., 1997, CRC Press, Boca Ratón Florida, and the references mentioned in it, Solid Phase Peptide Synthesis: A Practical Approach, Atherton &Sheppard, Eds., 1989, IRL Press, Oxford, England, and the references mentioned therein). Otherwise, the peptides of the invention can be prepared by segment condensation, as described for example in Liu et al., 1996, Tetrahedron Lett. 37 (7): 933-936; Baca, et al., 1995, J. Am. Chem. Soc. 117: 1881-1887; Tam et al., 1995, Int. J. Peptide Protein Res. 45: 209-216; Schnolzer and Kent, 1992, Science 256: 221-225; Liu and Tam, 1994, Proc. Nati Acad. Sci, USA 91: 6584-6588; Ya ashiro and Li, 1988, Int. J. Peptide Protein Res. 31: 322-334). The condensing of the segment is a particularly useful method to synthesize the modalities that contain internal glycine residues. Other useful methods for synthesizing the peptides of the invention are described in Nakagawa et al., 1985, J. Am. Chem. Soc. 107: 7087-7092. ApoA-I agonists containing blocking groups at the N and / or C-terminus can be prepared using the normal techniques of organic chemistry. For example, methods for acylation of the N-terminus of a peptide or the amidation or esterification of the C-terminus of a peptide are well known in the art. The modes of making other modifications in the N and / or C-terminal will be apparent to those skilled in the art, as will the ways of protecting any of the sidechain functionalities as necessary to join the terminal blocking groups. The pharmaceutically acceptable salts (against ions) can be conveniently prepared by ion exchange chromatography or other methods well known in the art. The compounds of the invention which are in the form of cascade multimers can be conveniently synthesized by adding the linker (s) to the peptide chain at the appropriate step in the synthesis. Else, the helical segments can be synthesized and each segment reacted with the linker. Of course, the actual synthesis mode will depend on the composition of the linker. Suitable protection schemes and chemistries are well known, and will be apparent to those skilled in the art. The compounds of the invention which are in the form of branched networks can be conveniently synthesized using the trimeric and tetrameric resins and the chemistries described in Tam, 1988, Proc. Nati Acad. Sci. USA 85: 5409-5413 and Demoor et al., 1996, Eur. J. Biochem. 239: 74-84. The modification of the synthetic resins and the strategies for synthesizing branching networks of higher or lower order, or containing combinations of different helical segments of the core peptide are within the capabilities of those skilled in the art of peptide chemistry and / or organic chemistry The formation of disulfide bonds, if desired, is generally carried out in the presence of moderate oxidizing agents. It is possible to use chemical oxidizing agents, or the compounds can simply be exposed to atmospheric oxygen to effect these bonds. Different methods are known in the art, including those described, for example, in Tam et al., 1979, Synthesis 955-957; Stewart et al., 1984, Solid Phase Peptide Synthesis, 2nd edition., Pierce Chemical Company Rockford, IL; Ahmed et al., 1975, J. Biol. Chem. 250: 8477-8482; and Pennington et al., 1991 Peptides 1990 164-166, Giralt and Andreu. Eds., EXCMO. Leiden, The Netherlands. A further alternative is described in Kamber et al., 1980, Helv. Chim. Act 63: 899-915. A method performed on solid supports is described by Albericio, 1985, Int. J. Peptide Protein Res. 26: 92-97. Any of these methods can be used to form disulfide bonds in the peptides of the invention. . 2.2 RECOMBINANT SYNTHESIS If the peptide is completely amino acids encoded by genes, or a portion of them is thus composed, the peptide or the relevant portion can also be synthesized using conventional recombinant genetic engineering techniques. For recombinant production, a polynucleotide sequence encoding the peptide is inserted into a suitable expression vehicle, i.e., a vector containing the necessary elements for the transcription and translation of the inserted coding sequence, or in the case of a vector of viral RNA, the necessary elements for replication and translation. The expression vehicle is then transfected into a suitable target cell that will express the peptide. Depending on the expression system used, the expressed peptide is then isolated by methods well established in the art. Methods for production of protein and recombinant peptides are well known in the art (see, for example, Sambrook et al., 1989, Molecular Cloning A Laboratory, NY; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Greene Publishing Associates and Wiley Interscience, NY each of which is incorporated as a reference in its integrity). To increase the efficiency of production, the polynucleotide can be designed to encode multiple units of the peptide separated by enzymatic cleavage or cleavage sites, homopolymers (repeating peptide units) or heteropolymers (different peptides chained together) can be designed in this way . The resulting polypeptide can be unfolded (for example, by treatment with the appropriate enzyme) to recover the peptide units. This can increase the performance of the peptides driven by a single promoter.

In a preferred embodiment, a polycistronic polynucleotide can be designed so that a single mRNA is transcribed which encodes multiple peptides (ie, homopolymers or heteropolymers) each coding region operably linked to a cap-independent translation control sequence; for example, an internal ribosome entry site (IRES). When used in suitable viral expression systems, the translation of peptide encoded by the mRNA is directed internally in the transcript; for example, by the IRES. Thus, the polycistronic construct directs the transcription of a single large, polycistronic mRNA that, in turn, directs the translation of multiple individual peptides. This approach eliminates the production and enzymatic processing of the polyproteins and can significantly increase the performance of the peptides driven by a single promoter. It is possible to use different host-vector expression systems to express the peptides described herein. These include, but are not limited to, microorganisms such as bacteria transformed by recombinant bacteriophage DNA or plasmid DNA expression vectors containing an appropriate coding sequence, yeasts or filamentous fungi transformed with recombinant yeast expression or fungal vectors containing a coding sequence. adequate insect cell systems infected with recombinant virus expression vectors (eg, baculovirus) containing an appropriate coding sequence; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus or tobacco mosaic virus) or transformed with recombinant plasmid expression vectors (e.g., the Ti plasmid) containing a suitable coding sequence; or cell systems -animals. The expression elements of the expression systems vary in their length and specificities. Depending on the vector host system used, any of a number of transcription and translation elements, including constitutive and inducible promoters, can be used in the expression vector. For example, when cloning is carried out in bacterial systems, inducible promoters such as pL of bacteriophage?, Plac, ptrp, ptac (the ptrp-lac hybrid promoter) and the like can be used. When cloning is performed on insect cell systems, promoters such as the baculovirus polyhedron promoter can be used; When cloning is carried out in plant cell systems, it is possible to use promoters obtained from the genome of plant cells (for example, thermal shock promoters, the promoter for the small subunit of RUVISCO, the promoter for the chlorophyll binding protein a / b) or from plant viruses (for example, the 35F RNA promoter from CaMV, the TMV shell protein promoter) can be used; when performing screening in mammalian cell systems, promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or mammalian virus (e.g., the adenovirus late promoter; the promoter of the vaccine virus of 7.5 K) can be used; When cell lines containing multiple copies of the expression product are generated, it is possible to use the vectors based on SV40, BPV and EBV with a suitable selectable marker. In cases where plant expression vectors are used, the expression of the sequences encoding the peptides of the invention can be obtained by any of the different promoters. For example, it is possible to use viral promoters such as the RNA 35S and 17S RNA promoters of CaMV (Brisson et al., 1984, Nature 310: 511-514), or the TMV coat protein promoter (Takamatsu et al., 1987, EMBO J. 6: 307-311); otherwise, it is possible to use promoters from lantas such as the small subunit of RUBISCO (Coruzzi et al., 1984, EMBO J. 2: 1671-1680, Broglie et al., 1984, Science 224: 838-843) or heat shock promoters, for example, hspl7.5-E or hspl7.3-B from soybeans (Girley et al., 1986, Mol Cell Cell Biol. 6: 559-565). These constructions can be introduced into plant cells using Ti plasmids, Ri plasmids, plant virus vectors, direct DNA transformation, microinjection, electroporation, etc. For reviews of these techniques see, for example, Weissbach & Weissbach, 1988, Methods for Plant Molecular Biology, Academic Press, NY, HIV Section, pp. 421-463; and Grierson & The coding sequence can be linked to an adenovirus transcription / translation control complex, for example, the late promoter and the tripartite leader sequence. This chimeric gene can then be inserted into the adenovirus genome by in vitro or in vivo recombination. The insertion of a non-essential region of the viral genome (for example, the El or E3 region) will give rise to a recombinant virus that is viable and capable of expressing the peptide in infected hosts. (For example, see Logan &Shenk, 1984, Proc. Nati, Acad. Sci. (USA) 81: 3655-3659). Otherwise, it is possible to use the 7.5K vaccine promoter (see, for example, Mackett et al., 1982, Proc. Nati. Acad.

Sci. (USA) 79: 7415-7419; Mackett et al., 1984, J. Virol. 49: 857-864; Panicali et al., 1982, Proc. Nati Acad. Sci. 79: 4927-4931). Other expression systems for producing the peptides of the invention will be apparent to those who have the skills in the art. . 2.3 PEPTIDE PURIFICATION The peptides of the invention can be purified by techniques known as reverse phase chromatography, high performance liquid chromatography, ion exchange chromatography, gel electrophoresis, affinity chromatography and the like. The actual conditions that are used to purify a specific peptide will depend, in part, on the synthesis strategy and the factors such as net charge, hydrophobicity, hydrophilicity, etc., and will be evident for those who have the skills in the technique. The multimeric, branched peptides can be purified, for example, by ion exchange or size exclusion chromatography. For purification by affinity chromatography, it is possible to use any antibody that binds specifically to the peptide. For the production of antibodies, different host animals, including but not limited to rabbits, mice, rats, etc., can be immunized by injection with a peptide. The peptide can be linked to a suitable carrier, such as BSA, by means of a side chain functional group or linkers linked to a side chain functional group. It is possible to use various adjuvants to increase the immune response, depending on the host species, which include but are not limited to Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oily emulsions, mollusc hemocyanin, dinitrophenol and potentially useful human adjuvants such as BCG (Bacillus Calmette-Guerin) and Corynebacterium parvum.

Monoclonal antibodies to a peptide can be prepared using any technique for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique originally described by Kohier and Milstein, 1975, Nature 256: 495-497, or Kaprowski, U.S. Patent No. 4,376,110 which is incorporated herein by reference; the human B-cell hybridoma technique (Kosbor et al., 1983; Immunology Today 4: 72; Cote et al., 1983, Proc. Nati, Acad. Sci. U.S.A. 80: 2026-2030); and the hybridoma technique with EBV (Cole et al., 1985, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., 99. 77-95 (1985)). In addition, the techniques developed for the production of "chimeric antibodies" (Morrison et al., 1984, Proc. Nati, Acad. Sci. USA 81: 6851-6855; Neuberger et al., 1984, Nature 312: 604-608; Takeda et al., 1985, Nature 314: 452-454, Boss, U.S. Patent No. 4,816,397; Cabilly, U.S. Patent No. 4,816,567, which are incorporated by reference herein) splicing the genes from an antibody molecule of appropriate antigenic specificity mouse together with genes of a human antibody molecule of suitable biological activity can be used. Or it is possible to prepare "humanized" antibodies (see, for example, Queen, U.S. Patent No. 5,585,089 which is incorporated herein by reference). Otherwise, it is possible to adapt the techniques described for the production of single chain antibodies (U.S. Patent No. 4,946,778) to produce the peptide-specific single chain antibodies. Antibody fragments containing deletions of the specific binding sites can be generated by known techniques. For example, these fragments include, but are not limited to, F (ab ') fragments, which can be produced by ingesting pepsin from the antibody molecule and Fab fragments, which can be generated by reducing the disulfide bridges of the fragments. F (ab ') 2. Otherwise, it is possible to construct Fab expression libraries (Huse et al., 1989, Science 246: 1275-1281) to allow rapid and easy identification of the Fab monoclonal fragments with the desired specificity for the peptide of interest. The antibody or antibody fragment specific for the desired peptide can be bound, for example, to agarose, and the antibody-agarose complex is used in the immunochromatography to purify the peptides of the invention. See, Scopes, 1984, Protein Purification: Principles and Practice, Springer-Verlag New York, Inc., NY, Livingstone, 1974, Methods In Enzymology: Immunoaffinity Chromatography of Proteins 34: 723-731. . 3. PHARMACEUTICAL FORMULATIONS AND METHODS OF TREATMENT The ApoA-I agonists of the invention can be used to treat any abnormality in animals, especially mammals, including humans, for which the increase in HDL concentration in serum is beneficial. activation of LCAT and the stimulation of cholesterol effusion and the RCT. These conditions include, but are not limited to, hyperlipidemia, and especially hypercholesterolemia, and in cardiovascular diseases such as atherosclerosis (including the treatment and prevention of atherosclerosis); restenosis (for example, the prevention or treatment of atherosclerotic plaques that develop as a result of medical procedures such as balloon angioplasty); and other abnormalities, such as endotoxemia, which often gives rise to septic shock. It is possible to use ApoA-I agonists alone or in treatment in combination with other medications used for the aforementioned conditions. These treatments include, but are not limited to, simultaneous or sequential administration of the drugs involved. For example, in the treatment of hypercholesterolemia or atherosclerosis, the formulations of ApoA-I agonists can be administered with any of one or more cholesterol lowering treatments currently in use; for example, bile acid resins, niacin and / or statins. Such a combined regimen can produce particularly beneficial therapeutic effects since each drug acts on a different target in the synthesis and transport of cholesterol; that is, the bile acid resins affect the recycling of cholesterol, the population of kilomicron and LDL; niacin mainly affects the population of VLDL and LDL; statins inhibit cholesterol synthesis, decreasing the LDL population (and perhaps increasing the expression of the LDL receptor); whereas the ApoA-I agonists affect the RCT, increase the HDL, increase the activity of LCAT and favor the effusion of cholesterol. In another embodiment, ApoA-I agonists can be used together with fibrides to treat hyperlipidemia, hypercholesterolemia and / or cardiovascular diseases such as atherosclerosis. In yet another embodiment, the ApoA-I agonists of the invention can be used in combination with the anti-microbial and anti-inflammatory agents currently used to treat endotoxin-induced septic shock. The ApoA-I agonists of the invention can be formulated as peptides or as peptide-lipid complexes that can be administered to individuals in different ways to deliver the ApoA-I agonist to the circulation. Exemplary formulations and treatment regimens are described below. c * 5 5.3.1 ApoA-I AGONISTS AND PEPTIDE / LIPID COMPLEX AS ACTIVE INGREDIENT ApoA-I agonist peptides can be synthesized or manufactured using any of the techniques described in section 5.2 and its subsections. The preparations Stable which have a prolonged storage life can be prepared by lyophilizing the peptides, preparing a bulk for reformulation, or preparing individual aliquots or dosage units that can be reconstituted by rehydration with sterile water or a buffer solution, sterile, suitable before administration to an individual. In certain embodiments, it may be preferable to formulate and administer the ApoA-I agonist, in a peptide / lipid complex. This approach has some advantages since the complex must have an increased half-life in the circulation, particularly when the complex has a size and density similar to HDL and especially the pre-β-1 or pre-β-2 HDL populations. The lipid / peptide complexes can be conveniently prepared by any of the different methods described below. Stable preparations having a prolonged storage life can be prepared by lyophilization, the preferred method being the co-lyophilization process described below. The lyophilized peptide / lipid complexes can be used to prepare bulk for pharmaceutical reformulation, or to prepare individual aliquots or dosage units that can be reconstituted by rehydration with sterile water or a suitable buffered solution prior to administration to an individual. It is possible to use a number of methods well known to those skilled in the art to prepare vesicles or peptide-lipid complexes. For this purpose, some techniques for preparing liposomes or proteoliposomes are available and can be used. For example, the peptide can be co-sonified (using a bath sonator or probe) with the appropriate lipids to form the complexes. Otherwise, the peptide can be combined with the preformed lipid vesicles resulting in the spontaneous formation of the peptide-lipid complexes. In still another alternative, the peptide-lipid complexes can be formed by a detergent dialysis method; for example, a mixture of the peptide, lipid and detergent is dialyzed to remove the detergent and reconstitute or form the peptide-lipid complexes (e.g., see Jonas et al. 1996, Methods in Enzymol. 128: 553-582). Although the above methods are possible, each method has its own particular production problems in terms of cost, performance, reproducibility and safety. Applicants have developed a simple method for preparing the peptide or protein-phospholipid complexes which have characteristics similar to HDL. This method can be used to prepare complex ApoA-I-lipid peptides, and has the following advantages: (1) most or all of the included ingredients are used to form the designed complexes, thus avoiding wasting of the initial material that is common in other methods. (2) Freeze-dried compounds are formed which are very stable during storage. The resulting complexes can be reconstituted immediately before use. (3) Usually, the resulting complexes do not require further purification after training or before use. (4) toxic compounds are avoided, including detergents such as cholate. In addition, the production method can easily be scaled and is suitable for manufacturing by GMP (ie, in an environment without endotoxins). According to the preferred method, the peptide and lipid are combined in a solvent system which co-solubilizes each of the ingredients and can be completely removed by lyophilization. For this purpose, the pair of solvents must be carefully selected to guarantee the co-solubility of the antipathetic peptide and the lipid. In one embodiment, the protein (s) or peptide (s) to be incorporated into the particles can be dissolved in an aqueous or organic solvent or solvent mixture (solvent 1). The (phospho) lipid component is dissolved in an aqueous or organic solvent or solvent mixture (solvent 2) that is miscible with solvent 1, and the two solutions are combined. Otherwise, the peptide and the lipid can be incorporated into a co-solvent system, i.e., a mixture of solvents. An adequate proportion of peptide (protein) to lipids is first determined empirically so that the resulting complexes possess the appropriate physical and chemical properties; that is, usually (but not necessarily) similar in size to HDL. The resulting mixture is frozen and lyophilized to dryness. Occasionally, an additional solvent is added to the mixture to facilitate lyophilization. This lyophilized product can be stored for prolonged periods and will remain stable. In the working examples described infra, peptide 146 (SEQ ID NO: 146) and (phospho) lipids were dissolved separately in methanol, combined and then mixed with xylene before lyophilization. The peptide and lipid can be added to a mixture of the two solvents. Otherwise, a solution of the dissolved peptide (• in methanol it can be mixed with a solution of the lipid dissolved in xylene Care must be taken to avoid saline displacement of the peptide The resulting solution containing the peptide and lipid co-solubilized in methanol / xylene is lyophilized to form a powder. The lyophilized product can be reconstituted to obtain a solution or suspension of the peptide / lipid complex. To this end, the lyophilized powder is rehydrated with an aqueous solution at an adequate volume (frequently 5 mg peptide / ml which is suitable for intravenous injection). In a preferred embodiment, the The lyophilized powder is rehydrated with saline buffered with phosphates or a physiological saline solution. It is possible to have to stir the mixture or to subject it to vortex agitation to facilitate rehydration, and in most of the [* cases, the reconstitution step must be carried out at a temperature greater than or equal to the temperature of the phase transition of the lipid component of the complexes. In a few minutes a clear preparation of reconstituted protein-lipid complexes is obtained. It is possible to characterize an aliquot of the preparation Reconstituted, resulting, to confirm that the complexes in the preparation have the desired size distribution; for example, the size distribution of HDL. For this purpose it is possible to use gel filtration chromatography. In the working examples described infra, gel filtration chromatography with Superóse 6 FPLC from Pharmacia was used. The buffer used contains 150 mM NaCl in 50 mM phosphate buffer, pH 7.4. The common sample volume is 20 to 200 μl of the complexes containing 5 mg peptide / ml. The flow velocity in the column is 0.5 ml / min. A series of proteins of known molecular weight and diameter of stokes, as well as human HDL are used as standards to calibrate the column. Protein and lipoprotein complexes are monitored by absorbance or light scattering of wavelength 254 or 280 nm. The ApoA-I agonists of the invention can be complexed with a variety of lipids, including saturated, unsaturated, natural and synthetic lipids and / or phospholipids. Suitable lipids include, but are not limited to, phospholipids with small alkyl chains, egg phosphatidylcholine, soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, distearoyl phosphatidylcholine, 1-myristoyl-2-palmitoylphosphatidylcholine, 1-palmitoyl-2-myristoylphosphatidylcholine, -palmitoil-stearoyl-2, l-stearoyl-2-palmitoylphosphatidylcholine, dioleoilfosfatidiIcolina, dioleofosfatidiletanolamina, dilauroilfosfatidilglicerol phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, sphingolipids, phosphatidylglycerol, diphosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol, dimiristoilfosfatídico acid, palmitoilfosfatídico acid , dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylserine, dipalmitoylphosphatidylserine, brain phosphatidylserine, sphi Brain ngomielin, dipalmitolesphingomyelin, distearoylphingomyelin, phosphatidic acid, galactocerebrosides, gangliosides, cerebrosides, dilaurylphosphatidylcholine, (1,3) -D-mannosyl- (1,3) diglyceride, aminophenylglucoside, 3-cholesteryl-6 '- (glucosylthio) hexyl ether glycolipids, and cholesterol and its derivatives. Applicants have discovered that when the ApoA-I agonists of the invention are complexed with sphingomyelin, all HDLs are separated from the pre-β-type particles. Accordingly, in a preferred embodiment of the invention, ApoA-I agonists are administered as a complex with sphingomyelin. . 3.2 TREATMENT METHODS ApoA-I peptide agonists or peptide-lipid complexes of the invention can be administered by any suitable route that guarantees bioavailability in the circulation. This can best be achieved by parenteral routes of administration, including intravenous (IV), intramuscular (IM), intradermal, subcutaneous (SC) and intraperitoneal (IP) injections. For example, absorption through the digestive system can be achieved by oral administration routes (including but not limited to ingestion, buccal and sublingual) provided that suitable formulations (eg, enteric coatings) are used to avoid or reduce the minimal degradation of the active ingredient, for example, in severe environments of the oral mucosa, the stomach and / or the small intestine. Otherwise, administration by mucosal tissue such as vaginal and rectal administration modes can be used to avoid or minimize degradation in the gastrointestinal tract. In still another alternative, the formulations of the invention can be administered by transcutaneous (e.g., transdermal) routes, or by inhalation. It will be appreciated that the preferred route may vary with the condition, age and convenience of the container.

The actual dose of ApoA-I agonists or the peptide-lipid complex used will vary with the route of administration and should be adjusted to obtain circulating plasma concentrations of 100 mg / L to 2 g / L. The data obtained in animal model systems described herein show that the ApoA-I agonists of the invention associate with the HDL component, and have a predicted half-life in humans of about 5 days. Thus in one embodiment, ApoA-I agonists can be administered by injection at a dose between 0.5 mg / kg to 100 mg / kg once a week. In another embodiment, it is possible to maintain desirable serum concentrations by continuous intravenous or intermittent intravenous route to provide approximately 0.5-100 mg / kg / h. The toxicity and therapeutic efficacy of the different ApoA-I agonists can be determined using normal pharmaceutical procedures in cell cultures or experimental animals to determine the LD50 (the lethal dose for 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the LD50 / ED50 ratio. ApoA-I peptide agonists that exhibit large therapeutic indices are preferred. . 3.3 PHARMACEUTICAL FORMULATIONS The pharmaceutical formulation of the invention contains the peptide agonist of ApoA-I or the peptide-lipid complex as the active ingredient in a pharmaceutically acceptable carrier, suitable for administration and delivery in vivo. As the peptides may contain acidic and / or basic terminal and / or side chains, the peptides may be included in the formulations in any of the forms of free acids or bases, or in the form of pharmaceutically acceptable salts. Injectable preparations include sterile suspensions, solutions or emulsions of the active ingredient in aqueous or oily vehicles. The compositions also may contain formulatory agents, such as suspending, stabilizing and / or dispersing agents. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in t * multi-dose containers, and may contain preservatives added. Otherwise, the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to water, buffer, dextrose solution, pyrogen-free, sterile, etc., before use. For this purpose, the ApoA-I agonist can be lyophilized, or the co-lyophilized peptide-lipid complex can be prepared. The stored preparations may be supplied in unit dosage form and reconstituted before their use in vivo. For extended delivery, the active ingredient may be formulated as a depot preparation, for administration by implantation; for example, subcutaneous, intradermal or intramuscular injection. Thus, for example, the active ingredient can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives; for example, as a sparingly soluble salt form of the ApoA-I agonist. Otherwise, it is possible to use transdermal delivery systems manufactured as a disc or adhesive patch that slowly releases the active ingredient by percutaneous absorption. For this purpose, it is possible to use permeation enhancers to facilitate the transdermal penetration of the active ingredient. A particular benefit can be achieved by incorporating the ApoA-I agonists of the invention or the peptide-lipid complex into a nitroglycerin patch for use in patients with ischemic heart disease and hypercholesterolemia.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (for example pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler materials (for example, lactose, microcrystalline cellulose or calcium acid phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium starch glycolate); or wetting agents (for example sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product for constitution with water or other suitable vehicle before use. These liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives as suspending agents (eg, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (for example almond oil, oily esters, fractionated vegetable oils or ethyl alcohol); and preservatives (for example methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffers, flavors, colorants and sweetening agents as appropriate. Preparations for oral administration can be suitably formulated to obtain controlled release of the active compound. For buccal administration, the compositions may take the form of tablets or lozenges formulated in a traditional manner. For rectal and vaginal administration routes, the active ingredient may be formulated as solutions (for retention enemas), suppositories or ointments. For administration by inhalation, the active ingredient may be conveniently supplied in the form of an aerosol spray presentation of pressurized containers or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to supply a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a mixture of powders of the compound and a suitable powder base such as lactose or starch.

The compositions may, if desired, be presented in a container or dosing device which may contain one or more dosage unit forms containing the active ingredient. The package may, for example, comprise metal or plastic foil, such as a blister pack. The container or dosing device may be accompanied by instructions for administration. . 4. OTHER USES The ApoA-I agonists of the invention can be used in in vitro assays to measure HDL in serum, for example, for diagnostic purposes. Because ApoA-I agonists are associated with the HDL component of the serum, agonists can be used as "markers" for the HDL population. In addition, agonists can be used as markers for the sub-population of HDL that are effective in the RCT. For this purpose, the agonist can be added to or mixed with a patient's serum sample; after a suitable incubation time, the HDL component can be assayed by detecting the incorporated ApoA-I agonist. This can be carried out using labeled agonist (eg, radiolabels, fluorescent labels, enzyme labels, dyes, etc.), or by immunoassays using antibodies (or antibody fragments) specific for the agonist.

Otherwise, labeled agonists can be used in imaging procedures (eg, CAT scans, MRI scans) to visualize the circulatory system or to monitor the RCT, or to visualize HDL accumulation in fat bands, lesions atherosclerotic, etc. (where HDL must be active in the effusion of cholesterol). 6. EXAMPLE: SYNTHESIS OF THE PEPTIDE AGONISTS OF ApoA-I The peptides described in Table X (section 8.3, below) were synthesized and characterized as described in the following subsections. They were also analyzed structurally and functionally as described in sections 7 and 8 below. 6. 1 SYNTHESIS OF NUCLEO PEPTIDES Peptides were synthesized in solid phase according to the Merrifield technique (Merrifield, 1969, J. Am. Chem. Soc. 85: 2149-2154) using p-alkoxybenzylalcohol 0.25 mmol resin (HMP resin) (Wang, 1973, J.

Am. Chem. Soc. 95: 1328-1333) and the chemistry of Fmoc. All syntheses were performed on an automated peptide synthesizer Applied Biosystems ABI model 430A (Perkin Elmer, Foster City, CA). The solvation and activation times used for each coupling cycle are shown in Table V below: TABLE V CYCLES OF THE INDIVIDUAL COPULATION ACTIVATOR The resins were washed with NMP between each step of copulation. The protocol for a synthesis cycle is shown below in Table VI: TABLE VI COPULATION PROTOCOL FOR A SYNTHESIS CYCLE All amino acids except Fmoc-β- (1-naphthyl) alanine were coupled in this manner. The Fmoc-ß- (1-naphthyl) alanine was manually coupled. For the manual coupling Fmoc-ß- (1-naphthyl) alanine 1 mmol and 2- (lH-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (TBTU) 1 mmol tetrafluoroborate were dissolved in 5 ml of NMP and mixed with, the peptide-resin. Then, 2 mmol of N-ethyldiisopropylamine were added, the mixture was stirred for two hours and the peptide-resin was washed six times with 10 ml of NMP. The efficiency of the coupling was monitored using the Kaiser test (Kaiser, 1970, Anal. Biochem.34: 55577), and copulation was repeated if necessary. After copulation of naphthylalanine, the rest of the synthesis was performed automatically as already described. 6. 2 SYNTHESIS OF AMIDAS PEPTIDE Where indicated in Table X (section 8.3, infra), the peptide amides were synthesized using a Rink amide resin containing the handle Fmoc-Rink amide 4- (2 ', 4'-dimethylphenyl) Fmoc-phenoxymethyl (Rink, 1987, Tetrahedron Lett, 28: 3787-3790) and the synthesis protocols described in section 6.1 above. 6. 3 SYNTHESIS OF APPLIED PEPTIDES IN THE N TERMINAL Where indicated in Table X (section 8.3, infra), the N-terminal acylated forms of the peptides were prepared by exposing the peptide bound to the resin prepared as described in section 6.1. or 6.2, supra, to an appropriate acylating agent. For the N-terminal acylated peptides, 15 ml of acetic anhydride solution (10% v / v in NMP) was added to each 1 g of the peptide bound to the resin, the mixture was stirred for 5 minutes and the resin recovered by filtration. . The recovered resin was washed three times with NMP (15 ml) and three times with ethanol (15 ml). 6. 4 DISSOCIATION AND DESPROTECTION 142 mM, pH 9.2) and buffer 2 (10 mM Na2HP04, pH 2.5). The HPLC separations were performed on Nucleosil 7C18 or Nucleosil 7C4 columns (Macherey and Nagel, Germany), 250 x 21 mm, at a flow rate of 8 ml / min. Gradient elution was performed using a mixture of 0.1% TFA in water (Solvent A) and 0.1% TFA in acetonitrile (Solvent B). The gradients used were adjusted to meet the needs of each peptide. 6. 6 CHARACTERIZATION The mass and amino acid analysis of the purified peptides described in section 6.5 were confirmed by mass spectrometry and amino acid analysis, respectively, as described below. Edman degradation was used for sequencing. 6. 6.1 LC-MS For the determination of the mass, a commercially available three-stage, quadruple mass spectrometer was used (standard TSQ 700, from Finnigan MAT, San José CA, EU). A Pneumatically Assisted Electro-Isolation Interface (ESI) was used for the introduction of the sample to the ionization source at atmospheric pressure of the mass spectrometer. The sprayer interface was operated at a positive potential of 4.5 kV. The 143 Steel capillarity temperature was maintained at 2 ° C while the collector was at 70 ° C. The positive ions generated by this ionic evaporation process entered the mass spectrum analyzer. The multiplier was set at 1000 V. The mass spectrum analyzer compartment was at 4E-6. All acquisitions were made in a resolution < lu The peptides were analyzed by direct infusion of the purified peptides using an ABI microperforation system (Applied Biosystems) consisting of a syringe pump (model 140B), a UV detector (model 785A) and an oven / injector (model 112A). The solvent system consisted of water (solvent A) and acetonitrile (solvent B), each containing 0.1% TFA. The peptides were injected using a gradient or isocratic conditions and eluted from an Aquapore C18 column. The flow rate was usually 300 μl / min. The concentration of each peptide was approximately 0.03 mg / ml, 20 μl of which was injected (eg, 30 pmol). Full scan MS experiments were obtained by quadruple scanning 1 from m / z 500-1500 in 4 sec. The data was acquired using an Alpha DEC station and processed using the software package provided by Finnigan MAT (BIOWORKS). 144 6. 6.2 AMINO ACID ANALYSIS The amino acid analysis was performed on an ABI 420 amino acid analyzer (Applied Biosystems). This system consists of three modules: a hydrolysis and derivation instrument, a reverse phase HPLC and a data system.

The peptide sample was applied (three times in triplicate) on porous glass coverslips and subsequently hydrolyzed under gas phase conditions (155 ° C, 90 min), After elimination of HCL, the resulting amino acids were converted to PTC-AA (phenylthiocarbamoyl-amino acids) using PITC (phenylisothiocyanate). After transfer to the HPC sample loop, the resulting mixtures were fractionated on a Aquapore C18 column using the gradient mode (Solvent A: ammonium acetate (NH4Ac) 50 mmol, pH 5.4, in water; Solvent B: 32 mmol acetal sodium (NaOAc) in aqueous acetonitrile) under conditions of temperature control. The HPLC data was processed by the software package provided by Applied Biosystems. The quantification was performed in relation to the standard peptide provided by Applied Biosystems. 6. 7 SYNTHESIS OF BRANCHED NETS The tetrameric core peptidyl resin and the trimeric resin-peptidyl nucleus are synthesized as described 145 in Demoor et al., 1996, Eur. J. Biochem. 239: 74-84. The matrix of the tetrameric and trimeric core remained bound to the 4-methylbenzhydrylamine resin and then used as the initial peptidyl-resin for the automated synthesis of the core peptides as already described. Branched networks containing helical segments of different amino acid compositions can be synthesized using orthogonal synthesis and protection strategies, well known in the art. 10 7. EXAMPLE: STRUCTURAL AND LIPID UNION ANALYSIS OF THE ApoA-I PEPTIDES The structural and lipid binding characteristics of the purified peptides, synthesized as described in section 6, supra, were determined by circular dichroism (CD), fluorescence spectroscopy and nuclear magnetic resonance (NMR). 7. 1 CIRCULAR DICHROSIS 20 This example describes a preferred method for determining the degree of helicity of the core peptides of the invention, free in buffer and in the presence of lipids. 7.1.1 EXPERIMENTAL METHOD 146 The spectrum of circular dichroism in the far UV was recorded between 190 and 260 nm (in increments of 0.5 nm or 0.2 nm) with an AVIV62DS spectrometer (AVIV Associates, Lakewood, NJ, USA) equipped with a thermoelectric cell support and a heat exchanger. samples The instrument was calibrated with (+) - 10-camphoric acid. Between 1 and 3 scans were collected for each sample, using Suprasil quartz cells of 10 cm, 5 cm, 1 cm and 0.1 cm in length, respectively, for peptide concentrations of 10 -7 M to 10-4 M. The width band was set at 1.5 nm and the sweep speed at ls per wavelength step. The reported data 'is the average of at least 2 or 3 independent measurements. After subtraction of the bottom, the spectrum was _2 converted into molar ellipticity (?) Per residue in cm -i dmol degree. The concentration of the peptide was determined by amino acid analysis and also by absorption spectrometry in a Perkin Elmer Lambda 17 UV / Visible photometer spectrum when the peptide contained a chromophore (tryptophan, dansyl, naphthylalanine). The CD spectrum was obtained with free peptide, not bound (5 μM in 5 mM phosphate buffer, pH 7.4); with peptide-SUV complexes (20: 1 EPC: Chol, Ri = 30 and Ri = 50); with peptide-micelle complexes (l-myristoyl-2-hydroxy-sm-glycero-3-phosphatidylcholine, Ri = 100); and with free peptide, not bound in 147 presence of 2,2,2-trifluoroethanol) (TFE) (peptide 5 μM, 90% vol TFE). The SUVs were obtained by dispersing the lipids (10 mM, R. 20: 1 EPC: Chol., Avanti Polar Lipids, AL) in buffer phosphates (5 mM, pH 7.4) with bubbling N2 for 5 minutes, followed by sonification (1.5 hr) in a sonification bath. The homogeneity of the preparation was checked by FPLC. The micelles were obtained by dispersing the 6 mM lipid (1-myristoyl-2-hydroxy-sn-glycero-3-phosphatidylcholine, Avanti Polar Lipids, AL) in phosphate buffer (5 mM, pH 7. 4) with N2 bubbling for 5 minutes, followed by vortexing. To obtain the peptide-SUV complexes, the SUVs were added to the peptide (5 μM in 5 mM phosphate buffer, pH 15 7.4) at a phospholipid-peptide molar ratio (Ri) of 30 or 50. To obtain the peptide-micelle complexes , the micelles were added to the peptide (5 μM in phosphate buffer 5 _ mM, pH 7.4) in a Ri of 100. 20 The entire spectrum was recorded at 37 ° C. 7. 1.2 DETERMINATION OF HELICITY The degree of helicity of the peptides in the different conditions was determined from the helipticity average residues at 222 nm (Chen et al., 1974 148 Biochemistry 13: 3350-3359) or by comparing the CD spectrum obtained with the reference spectrum available in databases (reference spectrum 16 helical from Provencher &Glockner, 1981, Biochemistry 30: 33-37, denatured protein reference spectrum de Venyaminov et al., 1993, Anal. Biochem 214: 17-24) using the CONTIN curve fitting algorithm, version 2DP, 1 CD package (August 1982) (Provencher, 1982, Comput. Phys. : 213-227, 229-242). The acceptable fit was determined using the statistical analysis methodology provided by the CONTIN algorithm. The error of all methods was ± 5% of helicity. / Peptide 146 (SEQ ID NO: 146) contains a very high helical content (86% helicity) in buffer at a concentration of 5 μM. the helicity of peptide 146 (SEQ ID NO: 146) increases in the presence of SUVs (100% helicity) and micelles (100% helicity) and also in the presence of TFT (95% helicity), which is a solvent that, because it has a significantly lower dielectric constant (e = 26.7) than the Water (e = 78.4) stabilizes the helices a and intrapeptide hydrogen bonds in concentrations between 5-90% (v / v). With regard to TABLE X, section 8.3, infra, it can be observed that peptides that exhibit a high degree of activity of the LCAT (> 38%) generally have a structure of 149%. significant helical in the presence of lipids (> 60% helical structure in the case of unblocked peptides containing 22 or more amino acids or blocked peptides ft containing 18 or less amio acids;> 40% helical structure in the case of unblocked peptides containing 18 or less amino acids), while peptides that show little or no activation of the LCAT have little helical structure. However, in some cases, peptides that contain a helical structure Significant presence of lipids does not show significant activation of LCAT. As a consequence, the ability of the melanose peptides of the invention to adopt a helical structure in the presence of lipids is considered a crusial characteristic of the peptides. nucleus of the invention, since the ability to form a helix a in the presence of lipids seems to be a prerequisite for the activation of the LCAT. 7. 2 FLUORESCENCE SPECTROSCOPY 20 The lipid binding properties of the peptides synthesized in Section 6, supra, were tested by fluorescence measurements with labeled peptides, in the present case tryptophan (Trp or W) or Naphthylalanine (Nal). The fluorescence spectrum was recorded in a Fluoromax of Spex (Jobin-Yvon) "equipped with a 150W Xenon lamp, 150 two monochromators (of excitation and emission), a photomultiplier R-928 for detection, sensitive in red up to 850 nm and a thermoelectric cell support with magnetic stirring. For the measurements, Suprasil Quartz cuvettes were used in the micromolar concentration range. A device with variable slots (from 0.4 to 5 nm) allows the modulation of the incident and emitted intensities according to the concentration of the peptide used. The values reported are, in general, the average of between 2 to 4 spectra. The concentration of the peptide is determined by absorption spectrometry on a Philips PU 8800 using the absorption band of Trp (e280 nm = 5.550 M ~ 1cm "1 in Tris-buffer) or Nal (e224 nm = 92.770 M_1cm_1 in methanol). The fluorescence spectra of the peptides were recorded between 290 nm and 450 nm in Tris-HCl buffer solution (20 mM, pH = 7.5), in the presence and absence of lipid vesicles Small unilamellar vesicles were formed after rehydration in buffer solution of the lyophilized phospholipids, the dispersion and sonification under a stream of N2 The lipids used were PC of Egg / Chol. (20: 1) or POPC / Chol. (20: 1) .The spectra were recorded at a concentration of the peptide of 2 μM and at a temperature of 37 ° C. The fluorescence reference standard in case 151 of Trp was N-acetyltriptofanilamide (NATA). Lipid binding studies were performed by the progressive addition of lipid vesicles to the peptide in 2 μM solution (slots: 5nm in excitation and 1.5 nm in emission). The effects of dilution were taken into account for the determination of fluorescence intensity. Lipid concentrations were varied from 10 to 600 μM and the molar ratio of the lipid to the peptide (Ri) ranged from 5 to 300. The excitation wavelength was set at 280 nm for both Trp and Nal. 7. 2.1 SPECTRAL ANALYSIS OF FLUORESCENCE The data was directly recorded and processed by an IBM PC linked to the spectrofluorimeter through Spex's DM3000F software. The spectra were corrected by subtraction of the contribution of the solvent and by application of a coefficient determined by the constructor taking into account the variation of the response of the photomultiplier against the wavelength. The fluorescence spectra of the peptides were characterized by the wavelength at its maximum fluorescence emission and by its quantum yield compared to NATA in the case of peptides labeled with a tryptophan. The process of binding to lipids was analyzed by calculating the displacement of the wavelength in the 152 maximum fluorescence emission, (? max), and the variation of the relative fluorescence intensity of emission against the concentration of the lipid. The relative fluorescence intensity is defined as the following ratio: (I-Io)? Ma? / Io? Max- I e what are measured in the (? Max) corresponding to the initial free state of the peptide, ie without lipids. I is the intensity at a defined lipid to peptide ratio and it is the same parameter measured in the absence of lipids. The absence of these variations is important in the absence of interactions of the peptides with the lipids. 7. 2.2 RESULTS AND DISCUSSION The properties of binding peptide lipids 149 (PVLELFENLWERLLDALQKKLK; SEQ ID NO: 149) which is similar in the primary sequence to peptide 146 (SEQ ID NO: 146) except that it contains a W (TRP) residue at position 10, are presented in Table VII. 153 TABLE VII PEPTIDE UNION PROPERTIES 149 (SEQ ID NO: 149) TO LIPIDIC VESICLES MEASURED BY FLUORESCENCE Molar ratio Lipid: I / lo? Max (nm) Peptide (Ri) 0 0 347 5 19.7 334.5 10 31.4 329 30 49.4 325.5 60 64.3 325 100 77 325.5 200 84 325 In buffer solution, at a concentration of 2 μM, the maximum fluorescence emission of tryptophan (? Max) from peptide 149 (SEQ ID NO: 149) is 347 nm. This corresponds to a tryptophan that is relatively exposed to the aqueous environment when compared to NATA (? Max = 350 nm). The peptide 149 (SEQ ID NO: 149) binds very efficiently to EPC / chol (20: 1) of small unilamellar vesicles as demonstrated by the concealment of tryptophan (the wavelength for the displacements of the maximum fluorescence emission for the tryptophan 347 nm to 345 nm) and the high exaltation of the fluorescence intensity (see Table VII). Concealment of the tryptophan residue is maximum for a lipid to peptide molar ratio of about 30. Other peptides that exhibit a high degree of helicity in the presence of lipids (> 60% for unblocked peptides of> 154 22 amino acids, or blocked peptides of < 18 amino acids; > 40% for unblocked peptides of < 18 amino acids) when measured by circular dichroism as described in section 7.1, above, also demonstrated good lipid binding. Of course, among all the peptides selected by circular dichroism detection, only those that can be followed by fluorescence were tested for their lipid binding properties. 7. 3 NUCLEAR MAGNETIC RESONANCE (NMR) This example describes an NMR method for analyzing the structure of the core peptides of the invention. 7. 3.1 SAMPLE PREPARATION FOR NMR Samples were prepared by dissolving 5 mg of peptide in 90% H2O / 10% D20 containing trace amounts of 2,2-Dimethyl-2-sila-5-pentane sulfonate (DSS) as a reference internal chemical shift. Some of the samples contained trifluoroethanol (TFE) (expressed as% by volume). The total volume of the sample was 500 μl and the concentration of the peptide was approximately 5 nM. 7. 3.2 NMR SPECTROSCOPY The H NMR spectra were acquired at 500 MHz using a Bruker DRX500 spectrometer equipped with a B-VT2000 temperature control unit. Uni and bi-dimensional experiments were recorded using standard pulse sequences. (Two Dimensional NMR Spectroscopy, Eds. W.R. Croasmun and RMK Carlson, 1994, VCH Publishers, New York, USA). The suppression of water was achieved with presaturation at low power for 2 seconds. Two-dimensional experiments were carried out in the phase sensitive mode using time proportional phase increment (TPPI) and a spectral width of 6000 Hz in both dimensions. Typically, 40 scans were co-added for 400 ti increments with 2048 data points. The data was processed using the FELIX95 (Molecular Simulations) software on an INDIG02 workstation (Silicon Graphics). The data was filled with zeros to obtain a data matrix 2K x 2K and apodized by a square function sine-bell displaced 45 °. 7. 3.3 ASSIGNMENT OF NMR Assignments of complete proton resonance were obtained by applying the sequence assignment technique using DQFCOSY, TOCSY and NOESY spectra as described in the literature (Wüthrich, NMR of Proteins and Nucleic Acids, 1986, John Wiley & amp; Sons, New York, EU). The secondary chemical shifts were calculated for protons HN and Ha subtracting the chemical shifts 156 random, tabulated helical (Wishart and Sykes, 1994, Method, Enx 239: 363-392) of the corresponding experimental values. (l 5 7.3.4 RESULTS AND ANALYSIS General Consideration Amphiphatic helical peptides tend to aggregate in aqueous solutions at the high concentrations required for NMR spectroscopy, making it difficult to obtain in the high resolution spectra.

For example, the NMR spectrum of the exemplary core peptide 146 (SEQ ID NO: 146) in water has very broad lines. Thus, the resonances of each amino acid residue can not be resolved. The addition of TFE to the sample improves the resolution of the spectra. The TFE is known for solubilizes the peptides, and further stabilizes the helical conformations of the peptides having a helical tendency. The NMR spectroscopy findings are demonstrated for peptide 4 (SEQ ID NO: 4) as a representative example. The 22-th Segrest consensus (SEQ) ID NO: 75) was studied in comparison. Chemical secondary displacements. The chemical shifts of the amino acid proton depend on the type of residue and the local secondary structure within a peptide or protein (Szlagyi, 1995, Progress in Nuclear Magnetic Resonance Spectroscopy 27: 325- 157 443). Therefore, the identification of the regular secondary structure is possible by comparing experimental displacements with tabulated values for random helical conformation. The formation of a helix a usually gives rise to a displacement above the field (negative) for the resonance Ha. The observation of the displacement H at the top of the field for various sequential residues is generally taken as evidence of a helical structure. The secondary H shifts for peptide 146 (SEQ ID NO: 146) in 25% TFE at 295 K show a significant negative shift for residues 4 to 19 (FIGURE 8A), demonstrating a highly helical conformation. The chemical shifts of the amide hydrogens of the amino acid residues residing in regions of the helix a also move upfield with respect to the chemical shifts that are observed for the random windings. In addition, it is possible to observe a periodicity of the HN displacements, and this reflects the period of the helicoidal turns. The amplitude of the variation of the displacement along the sequence is related to the amphipathicity of a helical peptide. A higher hydrophobic moment gives rise to a more pronounced oscillation (Zhou et al., 1992, J. Am. Chem. Soc. 114: 4320-4326). The secondary displacements HN for the 158 peptide 146 (SEQ ID NO: 146) in 25% TFE at 295 K show an oscillatory behavior according to the unfriendly nature of the helix (FIGURE 8B). The amino acid replacements give a more pronounced periodicity throughout the sequence (FIG 8B). The pattern clearly shows the stronger antipathetic nature of peptide 146 (SEQ ID NO: 146) compared to the 22-mer Segrest consensus (SEQ ID NO: 175). With reference to FIG. 8C, the distribution of the amino acids in an idealized helix, where the hydrophobic residues are shared and the hydrophilic residues are represented by clear circles, is plotted together with the secondary chemical shifts of the amide proton of peptide 146 (SEQ ID NO: 146). The experimental values are connected by a smoothed line for clarity. The displacements of the NMR determine the helical structure and the existence of 5-6 helicoidal turns can be discussed. The secondary displacement of a • amide proton is influenced by the length of the hydrogen bond to the carbonyl oxygen one turn away from the helix. So, the periodicity of the values observed for the chemical shift reflect different lengths of the hydrogen bond. This difference is associated with a general curved helical shape of the main chain of the 159 propeller. The hydrophobic residues are located on the concave side. The secondary displacements of peptide 146 (SEQ ID NO: 146) indicate a helical conformation < ß curve. 5 8. EXAMPLE: LCAT ACTIVATION TEST The peptides synthesized as described in section 6, supra furon analyzed in vitro for their ability to activate LCAT. In the LCAT assay, the vesicles The substrate (small unilamellar vesicles or "SUV") composed of egg phosphatidylcholine (EPC) or 1-palmitoyl-2-oleyl-phosphatidylcholine (POPC) and radiolabelled cholesterol are preincubated with equivalent masses of the peptide or ApoA-I (isolated from human plasma). The reaction is initiated by the addition of LCAT (purified from human plasma). The native ApoA-I that was used as a positive control represents activity of 100% activation. "Specific activity" (ie activity units (activation of the LCAT / mass unit) of the peptides can be calculated as the concentration of the peptide that achieves the maximum activation of the LCAT. For example, a series of peptide concentrations (eg, a limiting dilution) can be assayed to determine the "specific activity" for the peptide, the concentration that achieves maximum activation of the peptide. the LCAT (ie, the cholesterol conversion rate 160 to cholesterol ester) at a specific time point in the assay (for example one hour). When the cholesterol conversion percentage is plotted in, for example, one hour, against the concentration of the peptide used, the "specific activity" can be identified as the concentration of the peptide that reaches a constant in the plotted curve. 8. 1. PREPARATION OF SUBSTRATE VESICLES The vesicles used in the LCAT assay are SUVs composed of egg phosphatidylcholine (EPC) or 1-palmitoyl-2-oleyl-phosphatidylcholine (POPC) and cholesterol with a molar ratio of 20: 1. To prepare a sufficient vesicle standard solution for 40 trials, 7.7 mg of EPC (or 7.6 mg of POPC, 10 μmol), 78 μg (0.2 μmol of 4-14C-cholesterol, 116 μg of cholesterol (0.3 μmol) are dissolved in 5 ml of xylene and lyophilized, then 4 ml of the test buffer is added to the dehydrated powder and sonified under nitrogen atmosphere at 4 ° C. Sonification conditions: Branson 250 sonifier, 10 mm tip, 6.5 minutes; assay: 10 mM Tris, 0.14M NaCl, 1 mM EDTA, pH 7.4). The sonicated mixture is centrifuged six times for 5 minutes each time at 14,000 rpm (16,000 x g) to remove the titanium particles. The resulting clear solution is used for enzyme testing. 161 8. 2. LCAT PURIFICATION For the purification of LCAT, dextran sulfate / mg 2+ treatment of human plasma is used to obtain lipoprotein deficient serum (LPDS), which is subsequently subjected to chromatography on Phenylsepharose, Affigleblue, ConcanavalinA Sepharose and affinity chromatography anti-ApoA-I, as summarized for the representative purification in Table IX below: TABLE IX PURIFICATION OF LCAT Fraction V Voolluummeenn P Prrootteeíinnaa A Accttiivviiddaadd Performance Total total total purification (nmol (%) (parts) (ml) (mg) EC / mg * h) Plasma 550 44550 63706 LPDS 500 31000 62620 98 1.4 Phenil 210 363 51909 82 100 Sepharose Affigelblue 95 153 25092 39 115 ConA 43 36 11245 18 220 Sepharose Affinity 120 3.5 5500 9 1109 anti-A-1 8. 2.1 PREPARATION OF LPDS To prepare LPDS, 500 ml of plasma is added to 50 ml of dextran sulphate solution (MW = 500000). Stir for 20 minutes. Centrifuge for 30 minutes at 3,000 rpm (16,000 x g) at 4 ° C. Use the supernatant (LPDS) for 162 Greater purification (ca 500 ml). 8. 2.2. CHROMATOGRAPHY IN PHENYLSEPHAROSE The following materials and conditions were used for chromatography in phenylsepharose. Solid phase: fast-flow phenylsepharose, subst. high, Pharmacia Column: XK26 / 40, gel bed height: 33 cm, V = ca. 175 ml Flow rates: 200 ml / h (sample) Washing: 200 ml / h (buffer) Elusion: 80 ml / h (distilled water) Buffer: 10 mM Tris, 140 mM NaCl, lmM EDTA, pH 7.4, 0.01% sodium azide. Balance the column in tris-buffer solution, add 29 g of NaCl to 500 ml of LPDS and apply to the column. Wash with some volumes of Tris-buffered solution until the absorption at 280 nm wavelength is approximately at the base, then start elution with distilled water. The fractions containing the protein are combined (combined size: 180 ml) and used for chromatography on Affigelblue. 8. 2.3. CHROMATOGRAPHY IN AFFIGELBLUE The phenylsepharose combination is dialysed during the night at 4 ° C against 20 mM Tris-HCl, pH 7.4, 0.01% sodium azide. The combined volume is reduced by ultrafiltration (Amicon YM30) of 50-60 ml and loaded onto an Affigelblue column. Solid phase: Affigelblue, Biorad, column 153-7301, XK26 / 20, gel bed height: ca. 13 cm; volume of the column; approximately 70 ml. Flow rates: load: 15 ml / h Wash: 50 ml / h Balance the column with Tris-buffer. Apply the phenylsepharose combination to the column. Start in parallel to collect the fractions. Wash with Tris-buffer. The combined fractions (170 ml) were used for ConA chromatography. 8. 2.4. CHROMATOGRAPHY IN CONA The combination of Affigelblue was reduced through Amicon (YM30) at 30-40 ml and dialyzed against start buffer ConA starting with (Tris HCl lmM pH 7.4, MgCl 2 1 mM, MnCl 2 lmM, CaCl 2 lmM, 0.01% sodium azide) overnight at 4 ° C. Solid phase: Sepharose ConA (Pharmacia) Column: XK26 / 20, gel bed height: 14 cm (75 ml) Flow rates: loading 40 ml / h 164 Washing (with initial buffer): 90 ml / h Elusion: 50 ml / h, methyl-a-D-mannoside 0.2 M in Tris lmM, pH 7.4. The protein fractions of the mannoside elusions were collected (110 ml), and the volume was reduced by ultrafiltration (YM30) to 44 ml. The combination of ConA was divided into 2 ml aliquots, which were stored at -20 ° C. 8. 2.5. AFFIXITY CHROMATOGRAPHY ANTI-ApoA-I Affinity-ApoA-I affinity chromatography was performed on Affigel-Hz material (Biorad), to which the anti-ApoA-I abs had been covalently coupled. Column: XK16 / 20, V = 16 ml. The column was equilibrated with PBS pH 7.4. 2 ml of the combination of ConA were dialysed for two hours against PBS before loading on the column. Flow rates: load: 15 ml / hour, wash (PBS), 40 ml / hour. The combined protein fractions (V = 14 ml) are used for LCAT analysis. The column is regenerated with 0.1 M citrate buffer (pH 4.5) to elute the bound A-I (100 ml), and immediately after this procedure it is equilibrated with PBS. 8.3. RESULTS The results of the activation test of the LCAT are presented in Table X, infra.

TABLE X Activation of LCATs exhibiting exemplary core peptides 15 166 c « fifteen 167? > fifteen 168 15 the 22-mer Segrest consensus peptide (Anantharamaiah et al., 1990, t-teriosclerosis 10 (1): 95-105). 1fiQ fifteen 170 (9 [Au] -Peptide 22-mere consensus (Anantharamaiah et al., 1990, Arteriosclerosie 10 (1): 95-105). 171 G. 15 [R "J-peptide 22-mere consensus (Anantharamaiah et al., 1990, Arteriesclerosis 10 (1): 95-105). 172 15 17-. \ Z fifteen 174 fifteen 175 15 17fi fifteen 177 < ? * peptide? D-3 (Labeur et al., 1997, Arteriosclerosis, Thrombosis and Vascular Biology 17 (3): 580-588). ', Peptide AC-18AMOD-C (O) NH2 (Epand et al., 1987, J. Biol. Chem. 262 (19): 9389-9396). "Ac-18AM4-C (0) NH2 peptide (Brasseur, 1993, Biochim, Biophys, Acta 1170: 1-7). 178 * 18L peptide (Segrest et al., 1990, Proteins: Structure, Fuon and Genetics 8: 103-117). «Peptide 18A. { Anantharamaiah et al., 1985, J. Biol. Chem. 260 (18): 10248-10255). »J.8AM4 peptide (Rosseneu et al., W093 / 25581; Corijn et al., 1993, Biochim Biophys., Acta 1170: 8-16). 10 peptide [Glu1 '; Leus, "'") 18A (Epand et al., 1987, J. Biol. Chem. 262 (19): 9389-9396). 15"Ac-18AM3-C (0) NH2 (Roseeneu et al., W093 / 25581) 12 Ac-18AM2 ~ C (0) NH2 (Rosseneu et al., W093 / 25581)" Ac-18AM1-C (0 ) NH2 (Rosseneu et al., W093 / 25581). < * 17Q fifteen 180 In TABLE X, * denotes peptides that are acetylated at the N-terminus and amidated at the C-terminus; 'indicates peptides that are dansylated at the N-terminus; sp indicates peptides that presented solubility problems under the experimental conditions; X is Aib; Z is Nal; 0 is Orn; He (%) designates the percentage of helicity; mies designates micelles; and ~ indicates amino acid deletion. 9. EXAMPLE: PHARMACOKINETICS OF ApoA-I AGONISTS The following experiments can be used to demonstrate that ApoA-I agonists are stable in the circulation and are associated with the HDL component of the plasma. 9. 1 SYNTHESIS OF RADIOMARCED PEPTIDES The radiolabeled peptides are synthesized by coupling the labeled amino acid in C as the N-terminal amino acid. The synthesis is carried out according to Lapatsanis, Synthesis, 1983, 671-173 [sic]. In brief, 250 μM of unlabeled N-terminal amino acid is dissolved in 225 μl of 9% Na 2 C0 3 solution and added to a solution (Na 2 C 0 3 9%) of 9.25 MBq (250 μM) of 14 C-labeled N-terminal amino acid. The liquid is cooled to 0 ° C, mixed with 600 μM (202 mg) of 9-fluorenylmethyl-N-succinimidylcarbonate (Fmoc-OSu) in 0.75 ml of DMF and stirred at room temperature.

During 4 hours. After the mixture is extracted with diethyl ether (2 x 5 ml) and chloroform (1 x 5 ml), the remaining aqueous phase is acidified with 30% HCl and extracted with chloroform (5 x 8 ml). The organic phase is dried over Na 2 SO 4, filtered and the volume is reduced under nitrogen flow to 5 ml. The purity is estimated by TLC (CHC13: MeOH: Hac, 9: 1: 0.1 v / v / v, RPTLC in stationary phase with silica gel 60, Merck, Germany). The chloroform solution containing Fmoc-amino acid labeled with 1C is used directly for the synthesis of the peptides. A peptide resin containing 2-22 amino acids is synthesized automatically as described in section 6. The sequence of the peptide is determined by Edman degradation. The coupling is carried out as described in section 6.1. 9. 2 PHARMACOKINETICS IN MICE In each experiment, 2.5 mg / kg of the radiolabelled peptide is injected intraperitoneally into mice that are fed normal mouse food or modified atherogenic Thomas-Harcroft diet (giving rise to severely elevated VLDL and IDL cholesterol [sic]) ). Blood samples are taken at multiple time intervals for the assessment of radioactivity in plasma. 182 9. 3 STABILITY IN HUMAN SERUM The stability of the ApoA-I agonists of the invention in human serum is demonstrated as described below. 9. 3.1 EXPERIMENTAL METHODS 100 μg of peptide (prepared as described in section 9.1, above), mixed with 2 ml of fresh human plasma (at 37 ° C) and delipidated immediately (control sample) or after 8 days of incubation at 37 ° C (test sample). The delipidation is performed by extracting the lipids with an equal volume of chloroform: methanol 2: 1 (v / v). The samples are loaded on a reverse phase C18 HPLC column and eluted with a linear gradient (25-58% over 33 minutes) of acetonitrile (containing 0.1% TFA).

Elusion profiles are followed by absorbance (220 nm) and radioactivity. 9. 4 FORMATION OF PARTICLES TYPE PRE-ß 9.4.1 EXPERIMENTAL METHOD Human HDL is isolated by ultracentrifugation of KBr density at a density d = 1.21 g / ml to obtain a higher fraction followed by Super6se 6 gel filtration chromatography to separate the HDL of other lipoproteins. 183 The isolated HDL are adjusted to a final concentration of 1.0 mg / ml with physiological saline based on the protein content determined by the Bradford protein assay. A 300 μl aliquot is separated from the isolated HDL 14 preparation and incubated with 100 μl of the C-labeled peptide for two hours at 37 ° C. The five separate incubations are analyzed including a blank containing 100 μl of physiological saline and four dilutions of C-labeled peptide: (i) 0.20 μg / μl peptide: HDL, ratio = 1:15; (ii) 0.30 μg / μl peptide: HDL, ratio = 1:10; (iii) 0.60 μg / μl peptide: HDL, ratio = 1: 5; and (iv) 1.00 μg / μl peptide: HDL, ratio = 1: 3. After two hours of incubation, an aliquot of 200 μl of the sample (total volume = 400 μl) is loaded onto a Super6se 6 gel filtration column for lipoprotein separation and analysis, and 100 μl is used to determine radioactivity total charged in the column. 9. 5 ASSOCIATION OF ApoA-I AGONISTS WITH HUMAN LIPOPROTEINS 9.5.1 EXPERIMENTAL METHODS The ability of ApoA-I agonists to associate with human lipoprotein fractions is determined by incubating the C-labeled peptide with each class of lipoprotein (HDL, LDL and VLDL) and a mixture of the different classes of 184 lipoproteins. The HDL, LDL and VLDL are isolated by ultracentrifugation with density gradient KBr ad = 1.21 g / ml and purified by FPLC in size exclusion column, column Superóse 6B (chromatography is performed at a flow rate of 0.7 ml / min and a buffer solution of Tris lOmM (pH 8), 115 mM NaCl, 2 mM EDTA and 0.01% NaN3). The C-labeled peptide is incubated with HDL, LDL and VLDL at a peptide: phospholipid ratio of 1: 5 (mass ratio) for 2 h at 37 ° C. The amount of lipoprotein needed (volumes based on the amount needed to produce 1000 μg) is mixed with 0.2 ml of peptide standard solution (1 mg / ml) and the solution is brought to 2.2 ml using 0.9% NaCl After incubation for 2 hours at 37 ° C, an aliquot (0.1 ml) is separated for liquid scintillation counting to determine total radioactivity, the density of the remaining incubation mixture is adjusted to 1.21 g / ml with KBr, and the samples are centrifuged at 100,000 rpm ( 300,000 g) for 24 hours at 4 ° C in a TLA 100.3 rotor using a Beckman ultracentrifuge. The resulting supernatant is fractionated by removing 0.3 ml aliquots from the top of each sample for a total of five fractions, and 0.05 ml of each fraction is used for liquid scintillation counting. The two top fractions 185 they contain the floating lipoproteins, the other fractions (3-5) correspond to proteins / peptides in solution. 9. 6 ApoA-I AGONISTS OF THE INVENTION SELECTIVE UNION TO HDL LIPIDS IN HUMAN PLASMA 9.6.1 EXPERIMENTAL METHOD To demonstrate that the ApoA-I agonists of the invention bind selectively to HDL proteins in human plasma [sic], 2 ml of human plasma are incubated with 20, 40, 60, 80 and 100. μg of peptide labeled with 14C for two hours at 37 ° C. The lipoproteins are separated by adjusting the density to 1.21 g / ml and centrifugation in a rotor (TLA 100.3 at 100,000 rpm (300,000 g) for 36 hours at 4 ° C.) 900 μl is taken from the top (in 300 μl fractions) For the analysis, 50 μl of each 300 μl fraction is counted for radioactivity and 200 μl of each fraction is analyzed by FPLC (Superóse 6 / Superose 12 combined column).

. EXAMPLE: ApoA-I AGONISTS FAVOR THE EFUSION OF CHOLESTEROL to demonstrate that the ApoA-I agonists of the invention favor cholesterol effusion, HepG2 hepatoma cells are plated in 6-well culture plates and grown to confluence . The cells are marked 186 with 3H-cholesterol drying the cholesterol, then adding 1% bovine serum albumin (BSA) in phosphate-buffered saline (PBS), sonicating the solution and adding 0.2 ml of this marker solution and 1.8 ml of growth medium to the cells , so that each well contains 2 μCi of radioactivity. The cells are incubated for 24 hours with the labeling medium. The peptide (or protein): DMPC complexes are prepared at a 1: 2 peptide (or protein): DMPC (p: p) ratio. To prepare the complexes, the native human ApoA-I peptide or protein is added to a solution of DMPC in PBS and incubated at room temperature overnight, at which time the solution will be clarified. The concentration of the peptide or protein in the final solution is approximately 1 mg / ml. The labeling medium is separated from the cells and the cells are washed with PBS before the addition of the complexes. 1.6 ml of the growth medium are added to each well, followed by the peptide (or protein) complex: DMPC and enough PBS to carry a final volume of 2 ml per well. The final concentrations of the peptide or ApoA-I are approximately 1, 2.5, 5, 7.5 and 25 μg / ml of the medium. After 24 hours of incubation at 37 ° C, the medium is separated, and the cells are washed with 2 ml of BSA / 1% PBS, followed by two washes with 2 ml each of PBS. The 3 amount of H-cholesterol in the medium is determined by 187 of liquid scintillation. 11. EXAMPLE: USE OF ApoA-I AGONISTS IN ANIMAL MODEL SYSTEMS The efficacy of the ApoA-I agonists of the invention was demonstrated in rabbits. The results show that the administration of ApoA-I agonists increases the concentration of HDL type particles in serum. 11. 1 PREPARATION OF THE FOSFOLIPID / PEPTIDE COMPLEX Small discoid particles consisting of phospholipid (DPPC) and peptide 146 (SEQ ID NO: 146) were prepared following the cholate dialysis method. The phospholipid was dissolved in chloroform and dried under a stream of nitrogen. The peptide was dissolved in buffer (saline) at a concentration of 1-2 mg / ml. The lipid film was redissolved in cholate containing buffer (43 ° C) and the peptide solution was added to a 3: 1 phospholipid / peptide weight ratio. The mixture was incubated overnight at 43 ° C and then dialyzed at 43 ° C (24 h), room temperature (24 h) and 4 ° C (24 h), with three changes of buffer solution (large volumes) in the point of temperature. The complexes were sterilized by filtration (0.22 μm) for injection and storage at 4 ° C. 188 11. 2 ISOLATION AND CHARACTERIZATION OF THE PEPTIDE / PHOSPHOLIPID PARTICLES The particles were separated in a gel filtration column (Exceeded 6 HR). The position of the peak containing the particles was identified by measuring the concentration of the phospholipid in each fraction. From the volume of elusion, the Stokes radius could be determined. The concentration of the peptide in the complex was determined by determination of the phenylalanine content (by HPLC) after acid hydrolysis of 16 h. 11. 3 INJECTION IN THE RABBIT New Zealand rabbits, white, males (2.5-3 kg) were injected intravenously with a dose of the phospholipid / peptide complex (8 mg / kg body weight, expressed as peptide 146 (SEQ ID NO: 146 ) Or 10 mg / kg body weight of ApoA-I, expressed as peptide or protein content) in a single bolus injection not exceeding 10-15 ml. The animals were lightly sedated before manipulations. Blood samples (collected in EDTA) were taken before and 5, 15, 30, 60, 240 and 1440 minutes after the injection. For each sample the hematocrit (Het) was determined. Samples were aliquoted and stored at -20 ° C before analysis. 189 11. 4 ANALYSIS OF RABBIT SERIES Plasma lipids. Plasma cholesterol, plasma triglycerides and total plasma phospholipids were determined enzymatically using commercially available assays according to manufacturer's protocols (Boehringer Mannheim, Mannheim, Germany and Biomérieux, 69280, Marcy-1 'étoile, France) . Profiles for lipoprotein. The plasma lipoprotein profiles of the fractions obtained after plasma separation in their lipoprotein fractions were determined by centrifugation in a sucrose density gradient. The fractions were collected and in each individual fraction the content of phospholipid and cholesterol was measured enzymatically. 11. 5 RESULTS The lipoprotein profile of rabbits injected with 8 mg / kg of peptide 146 (SEQ ID NO: 146) (in the form of peptide / DPPC complexes) as a function of time is shown in Figure 9. A substantial increase in cholesterol of HDL cholesterol fractions (fractions> 1.06 mg / ml) is evident five minutes after injection and lasts approximately 24 hours. Cholesterol of the combined HDL fractions obtained by ultracentrifugation with density gradient 190 is presented in Table XI, below. The highest increase in HDL cholesterol (90%) occurred 240 min. after the administration. To the next 24 hours of the ÍG administration, the increase was still 71.2%. 5 These data indicate that the administration of peptide 146 / DPPC complexes (8 mg / kg) induces rapid and efficient mobilization of peripheral cholesterol.

TABLE XI 10 HDL CHOLESTEROL IN RABBITS AFTER ADMINISTRATION OF 8 mg / kg PEPTIDE 146 (SEQ ID NO: 146) or 10 mg / kg NA ApoA-I Time (min.) Increase in HDL Cholesterol (HDL cholesterol% (%) native ApoA-I) peptide 146 5 19.3 31.3 15 16 60.4 60 15.8 42.9 * Animal killed before the time indicated 15 12. EXAMPLE: PREPARATION OF THE PEPTIDE-LIPID COMPLEX BY THE CO-LIOFILIZATION METHOD The following protocol was used to prepare the peptide-lipid complexes. 191 One mg of peptide 146 (PVLELFENLWERLLDALQKKLK; SEQ ID NO: 146) peptide [sic] was dissolved in 250 μl of HPLC grade methanol (Perkin Elmer) in a small 1 ml clear glass bottle with lid (Waters # WAT025054). The dissolution of the peptide was with the aid of occasional vortex stirring for a period of 10 minutes at room temperature. To this mixture was added an aliquot containing 3 mg of dipalmitoyl-phosphatidylcholine (DPPC; Avanti Polar Lipids, purity 99%, product # 850355) of a standard solution of 100 mg / ml in methanol. The volume of the mixture was brought to 400 μl by the addition of methanol, and the mixture was further vortexed intermittently for a period of 10 minutes at room temperature. To each tube, 200 μl of xylene (Sigma-Aldrich, 99% purity, HPLC grade) were added and the tubes were vortexed for 10 seconds. Two small holes in the upper part of the tube were drilled into the tube stopper with a 20 gauge syringe needle, the tubes were frozen for 15 seconds in liquid nitrogen, and the tube was lyophilized overnight under vacuum. To the tube were added 200 ml of 0.9% NaCl solution. The tube was vortexed for 20 seconds. At this time the solutions in the tube were milky in appearance. The tube was then incubated in a water bath for 30 minutes at 41 ° C. The solutions became transparent (ie, 192 similar to water in appearance) after a few minutes of incubation at 41 ° C. 12. 1 CHARACTERIZATION OF THE COMPLEXES BY 5-FILTRATION CHROMATOGRAPHY IN SUPERPOSE GEL 6 The peptide-phospholipid complexes containing peptide 149 (SEQ ID NO: 149) labeled with 1C (specific radioactivity 159000 DPM / mg of peptide by weight, assuming 50% of peptide content 149) were prepared by freeze-drying as previously described. The preparation contained 1 mg of the peptide and 3 mg of DPPC by weight. After reconstituting the complexes in 200 μl of 0.9% NaCl, 20 μl (containing 100 μg of peptide 149) of the complexes were applied to a Super6se 6 column, Pharmacia using 0.9% NaCl as the liquid phase at a flow rate 0.5 ml / minute. Chromatography was monitored by absorbance or light scattering of wavelength 280 NM. One ml fractions were collected. Aliquots containing 20 μl of the fractions were assayed for 0 phospholipid content using the bioMerieux Phospholipides Enzymatique PAP 150 kit (# 61491) according to the instructions provided by the manufacturer. The vast majority of the phospholipid and UV absorbance were recovered together in some fractions with peaks in approximately 15.8 ml. 5 This volume of elusion corresponds to Stokes diameters 193 of 87 angstroms. For comparison, a separate chromatogram of 20 μl of human HDL2 was run under the same conditions and using the same column as the peptide 149 complexes. The HDL2 was prepared as follows: 300 ml of frozen human plasma (Mannheim Blutspendzentrale # 1185190) was thawed, adjusted to a density of 1.25 with solid potassium bromide and centrifuged for 45 hours at 40,000 rpm using a Ti45 (Beckman) rotor at 20 ° C. The floating layer was collected, dialyzed again with distilled water, adjusted to 1.07 density with solid potassium bromide and centrifuged as described above for 70 hours. The lower layer (at a level of 1 cm above the bottom of the tube) was collected, brought to 0.01% sodium azide and stored at 4 ° C for four days until chromatography. The eluate of the column was monitored by absorbance or light scattering of wavelength 254 nm. A series of proteins of known molecular weight and diameter Stokes were used as standard to calibrate the column for the calculation of Stokes particle diameters (Pharmacia Gel Filtration Calibration Kit Manual Instruction, Pharmacia Laboratory Separation, Piscataway, NJ, revised in April 1985). The HDL2 eluted with a retention volume of 14.8 ml, corresponding to a Stokes diameter of 108 nm. 194 EXAMPLE: PREPARATION OF ANTIBODIES In order to prepare antibodies of the ApoA-I agonists of the invention, the peptide is conjugated to mollusc hemocyanin (KLH, 1 mg of peptide at 10 mg of KLH). The KLH conjugate (LMG) was suspended in complete Freund's adjuvant and injected into rabbits at time 0, and started with 0.25 mg of KLH conjugate at four weeks and again at five weeks. Previous blood samples and blood samples after six weeks were tested for antibody titer against authentic antigen by ELISA. The blood samples from the production were combined from two rabbits. The antibodies directed exclusively against the peptide antigens were isolated as follows: 1. The free peptide was bound to Sepharose 4B activated with cyanogen bromide (Pharmacia according to the manufacturer's protocol). 2. The antisera were preabsorbed in a column of irrelevant peptides and in irrelevant mouse and human serum protein columns. 3. The preabsorbed antisera passed through the corresponding peptide column (see item 1). 4. The columns were washed with saline buffered with 0.1 M borate (pH 8.2) and the bound antibodies were eluted using a gradient step at low pH, from pH 195 4. 0 to pH 3.0 to pH 2.0 (0.1 M glycine buffer) and finally to 0.1 M HCl. 5. The eluate was neutralized with excess borate saline, concentrated by ultrafiltration (Amicon, YM30) and dialyzed against borate saline. 6. The protein concentration was determined by absorbance at 280 nm. The resulting antibodies were tested for species specificity using purified human ApoA-I or purified mouse ApoA-I in a direct ELISA binding assay. The invention is not limited in scope by the specific embodiments described which are proposed only as illustrations of the individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. In fact, some modifications of the invention, in addition to those shown and described herein, will be apparent to those skilled in the art from the aforementioned description and the accompanying drawings. Such modifications are proposed to fall within the scope of the appended claims. All references mentioned herein are incorporated by reference for all purposes. 196 LIST OF SEQUENCES (1) GENERAL INFORMATION < • (i) APPLICANT: Dasseux, Jean-Louis Sekul, Renate Buttner, Klaus Cornut, Isabelle Metz, Gunther 10 Dufourcq, Jean. (ii) TITLE OF THE INVENTION: AGOLISTS OF APOLIPOPROTEIN A-I AND ITS USE TO TREAT DISLIPIDEMIC CONCERNS 15 (iii) NUMBER OF SEQUENCES: 254 (iv) POSTAL ADDRESS (A): Pennie & Edmonds LLP 20 (B) STREET: 1155 Avenue of the Americas (C) CITY: New York (D) STATUS: NY (E) COUNTRY: EU (F) ZIP CODE: 10036-2811 25 197 (v): LEGIBLE COMPUTATION FORM: (A) TYPE OF MEDIA: floppy disk (B) COMPUTER: IBM compatible (C) OPERATING SYSTEM: DOS (D) SOFTWARE: FastSEQ Version 2.0 (vi) DATA OF THE CURRENT APPLICATION (A) APPLICATION NUMBER: PCT / US98 / 20326 (B) DATE OF: 28-SEP-1998 (C) CLASSIFICATION: / (vii) DATA FROM THE PREVIOUS APPLICATION (A) APPLICATION NUMBER: 08 / 940,096 (B) DATE OF: SEP 29, 1997 (viii) ATTORNEY / ATTORNEY INFORMATION (A) NAME: Coruzzi, Laura A (B) REGISTRATION NUMBER: 30,742 (C) REFERENCE / FILE NUMBER: 009196-0004-22Í (ix) TELECOMMUNICATIONS INFORMATION (A) TELEPHONE: 650-493-4935 (B) TELEFAX: 650- 493-5556 (C) TELEX: 66141 PENNIE 198 (2) INFORMATION OF SEQ ID NO: 1: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids V ", (B) TYPE: amino acid 5 (C) HEBRA: simple (D) TOPOLOGY: linear ( ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 10 (B) LOCATION: 16 (D) OTHER INFORMATION: Xaa = naphthylalanine (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 1: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Xaa 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 P 20 (2) INFORMATION FROM 'SEQ ID NO: 2: (i) CHARACTERISTICS OF THE SEQUENCE : (A) LENGTH: 23 amino acids (B) TYPE: amino acid (C) HEBRA: simple 25 (D) TOPOLOGY: linear 199 (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 2: Gly Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 5 1 5 10 15 Leu Lys Gln Lys Leu Lys Lys 20 (2) INFORMATION OF SEQ ID NO: 3: 10 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 15 (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Trp 20 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 4: 25 (i) CHARACTERISTICS OF THE SEQUENCE: 200 (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 4: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 23 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa = D-Pro 201 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 5: Xaa Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys Lys 20 (2) INFORMATION OF SEQ ID NO: 6: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRITION OF THE SEQUENCE: SEQ ID NO: 6: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 202 (2) INFORMATION OF SEQ ID NO: 7: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids - > (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 7: 10 Pro Val Leu Asp Leu Phe Lys Glu Leu Leu Asn Glu Leu Leu Glu Ala 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 15 (2) INFORMATION OF SEQ ID NO: 8: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 20 (C) HEBRA : simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 8: 25 203 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Gly Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 9: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 9: Pro Val Leu Asp Leu Phe Arg Glu Leu Gly Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 10: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: single 204 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 17 (D) OTHER INFORMATION: Xaa = naphthylalanine (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 10: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Xaa Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 11: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 11: 205 Pro Val Leu Asp Leu Phe Lys Glu Leu Leu Gln Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 12: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 12: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Gly Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 13: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 206 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 13: Gly Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Gly Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 14: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 18 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: other (B) LOCATION: 20 (D) OTHER INFORMATION: Xaa = Orn 207 (A) NAME / KEY: other (B) LOCATION: 22 (D) OTHER INFORMATION: Xaa = Orn (. (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 14: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Xaa Gln Xaa Leu Xaa 10 20 (2) INFORMATION OF SEQ ID NO: 15: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids 15 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 15: Pro Val Leu Asp Leu Phe Arg Glu Leu Trp Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 25 20 208 (2) INFORMATION OF SEQ ID NO: 16: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 16: Pro Val Leu Asp Leu Leu Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 17: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 17 209 Pro Val Leu Glu Leu Phe Lys Glu Leu Leu Gln Glu Leu Leu Glu Ala 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 18: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPpLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 18: Gly Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 19: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 210 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: fr (A) NAME / KEY: other 5 (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa = D-Pro (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 19: Xaa Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Gly Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 20: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid fr (C) HEBRA: simple 20 (D) TOPOLOGY: linear (ii) ) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 20: 211 Pro Val Leu Asp Leu Phe Arg Glu Gly Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys you. 20 5 (2) INFORMATION OF SEQ ID NO: 21: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 10 (C) HEBRA: simple (D) TOPpLOGY: linear (ii) ) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 15 (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa = D-Pro (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 21: fc Xaa Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 22: 212 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid tí (C) HEBRA: simple 5 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 22: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Gly 1 5/10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 23: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 20 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 23: 213 Pro Leu Leu Glu Leu Phe Lys Glu Leu Leu Gln Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 24: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: - linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 24: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 25: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 214 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 25: Pro Val Leu Asp Phe Phe Arg Glu Leu Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 26: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 26: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Leu 1 5 10 15 215 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 27: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 14 (D) OTHER INFORMATION: Xaa = naphthylalanine (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 27: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Xaa Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 28: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids 216 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 28: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Trp Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20. (2) INFORMATION OF SEQ ID NO: 29: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 29: Wing Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 217 (2) INFORMATION OF SEQ ID NO: 30: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids _r (B) TYPE: amino acid 5 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 10 (B) LOCATION: 1 ... 22 (D) OTHER INFORMATION: dansylated peptide in N / terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 30: 15 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys t 20 20 (2) INFORMATION FROM THE SEQ ID NO: 31: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 25 (C) HEBRA: simple 218 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (»(A) NAME / KEY: other 5 (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 31: Pro Val Leu Asp Leu Phe Leu Glu Leu Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 32: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid V (C) HEBRA: simple 20 (D) TOPOLOGY: linear (ii) ) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 25 (D) OTHER. INFO: Xaa = Aib 219 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 32: Xaa Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Ala. 1 5 10 15 5 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 33: (i) CHARACTERISTICS OF THE SEQUENCE: 10 (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 15 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 33 Pro Val Leu Asp Leu Phe Arg Glu Lys Leu Asn Glu -Leu Leu Glu Wing T, 1 5 10 15 20 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 34: (i) CHARACTERISTICS OF THE SEQUENCE: 25 (A) LENGTH: 22 amino acids 220 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 5 (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 5 (D) OTHER INFORMATION: Xaa = naphthylalanine (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 34: Pro Val Leu Asp Xaa Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 15 20 (2) INFORMATION OF SEQ ID NO: 35: (i) CHARACTERISTICS OF THE SEQUENCE: & (A) LENGTH: 22 amino acids 20 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 35: 221 Pro Val Leu Asp Trp Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 36: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 36: Pro Leu Leu Glu Leu Leu Lys Glu Leu Leu Gln Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 37: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 222 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 37: Pro Val Leu Asp Leu Phe Arg Glu Trp Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 38: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3Í 223 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Trp Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 39: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 39: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Leu Lys Wing 1 5 10 15 Leu Lys Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 40: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 224 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 40: Pro Val Leu Asp Leu Phe Asn Glu Leu Leu Arg Glu Leu Leu Glu Wing 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 41: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 41 225 Pro Val Leu Asp Leu Trp Arg Glu Leu Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 42: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 42: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Trp Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 43: 226 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 43: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Trp Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 44: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 227 (ix) PECULIARITY: (A) NAME / KEY: other (B) LOCATION: 1 ... 22 (D) OTHER INFORMATION: all genetically encoded amino acids are in the D configuration (A) NAME / KEY: other (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 44: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 45: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid / (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 228 (ix) PECULIARITY: (A) NAME / KEY: other (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 45: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 46: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 46: 229 Pro Val Leu Asp Leu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 47: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 47: Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Gly Leu Glu Ala Leu 1 5 10 15 Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 48: (i) CHARACTERISTICS OF THE SEQUENCE: "(A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 230 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (* (A) NAME / KEY: other 5 (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa = D-Pro (A) NAME / KEY: other (B) LOCATION: 2 10 (D) OTHER INFORMATION: Xaa = D-Val (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 48: Xaa Xaa Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 15 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 Tr (2) INFORMATION OF SEQ ID NO: 49: 20 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 25 (ii) ) TYPE OF MOLECULE: none 231 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 49: Pro Val Leu Asp Leu Phe Arg Asn Leu Leu Glu Lys Leu Leu Glu Wing 1 5 10 15 Leu Glu Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 50: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 50: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Trp Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 232 \ 2) INFORMATION OF SEQ ID NO: 51: (i) CHARACTERISTICS OF THE SEQUENCE:! (A) LENGTH: 22 amino acids fc (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear, 11) TYPE OF MOLECULE: none: IX) PECULIARITY: (A) NAME / KEY: other 10 (B) ) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib / xi DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 51 Pro Val Leu Asp Leu Phe Trp Glu Leu Leu Asn Glu Xaa Leu Glu Ala (B) TYPE: amino acid (C) HEBRA: simple 25 (D) TOPOLOGY: linear 233 (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: 1 (A) NAME / KEY: others I i (B) LOCATION: 13 i (D) OTHER INFORMATION: Xaa = Aib (xi |) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 52: Pro Val Trp Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Ala 1 '5 10 15 Leu Lys Gln Lys Leu Lys! twenty (2) INFORMATION OF SEQ ID NO: 53: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids j (B) TYPE: amino acid j (C) HEBRA: simple I (D) TOPOLOGY: linear (iii) ) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 53 Val Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 '5 10 15 234 Leu Lys Gln Lys Leu Lys 20 2) INFORMATION OF SEQ ID NO: 54: (i) CHARACTERISTICS OF THE SEQUENCE: 1 (A) LENGTH: 22 amino acids i (B) TYPE: amino acid I j (C) HEBRA: simple J (D) TOPOLOGY: linear I (iij) TYPE OF MOLECULE: none (xi DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 54 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Trp Leu Glu Wing 2) INFORMATION OF SEQ ID NO: 55: I (i) I CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 amino acids I I j (B) TYPE: amino acid I I (C) HEBRA: simple i | (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 235 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 55: Pro Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Ala Leu Lys Gln 1 1 5 10 15 Lys Leu Lys (2) INFORMATION OF SEQ ID NO: 56: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid I (C) HEBRA: simple (D) TOPOLOGY: linear (ii | ) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 56: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 1 ¡5 10 15 I I Leu Lys Gln Lys Lys Lys 20 (2) INFORMATION OF SEQ ID NO: 57: (i) I CHARACTERISTICS OF THE SEQUENCE: I I (A) LENGTH: 22 amino acids (B) TYPE: amino acid 236 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none living room j (B) LOCATION: 13 I I (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 58 237 Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu 20 (2) INFORMATION OF SEQ ID NO: 59: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 59: Leu Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 60: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 amino acids (B) TYPE: amino acid (C) HEBRA: simple 238 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none c (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 60: 5 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Ma 1 5 10 15 Leu Lys Gln (2) INFORMATION OF SEQ ID NO: 61: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 15 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other T, (B) LOCATION: 13 20 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 61: Pro Val Leu Asp Glu Phe Arg Trp Lys Leu Asn Glu Xaa Leu Glu Wing 25 1 5 10 15 239 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 62: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 62 Pro Val Leu Asp Glu Trp Arg Glu Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 63: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids 240 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION : Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 63: Pro Val Leu Asp Phe Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 64: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 241 (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 64: Pro Trp Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 65: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 12 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 65: 242 Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Ala Leu 1 5 10 15 Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 66: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPpLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 66: Pro Val Leu Asp Leu Phe Arg Asn Leu Leu Glu Glu Leu Leu Glu Wing 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 67: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) HEBRA: simple 243 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 67: Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Ala Leu 1 5 10 15 Lys Gln Lys Leu Lys 20 10 (2) INFORMATION OF SEQ ID NO: 68: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 15 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: fr (A) NAME / KEY: other 20 (B) LOCATION : 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 68: 244 Pro Val Leu Asp Glu Phe Arg Glu Leu Leu Lys Glu Xaa Leu Glu Wing 1 5 10 15 (2) INFORMATION OF SEQ ID NO: 69: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 10 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 15 (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 69: r. 20 Pro Val Leu Asp Glu Phe Arg Lys Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 70: 245 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 70: Pro Val Leu Asp Glu Phe Arg Glu Leu Leu Tyr Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 71: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 246 (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 14 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 71: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Leu Xaa Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20, (2) INFORMATION OF SEQ ID NO: 72: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 72: 247 Pro Val Leu / Asp Leu Phe Arg Glu Leu Leu Asn Glu Xaa Leu Trp Ma 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 73: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPpLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 73: Pro Val Leu Asp Glu Phe Trp Glu Lys Leu Asn Glu Xaa Leu Glu Ma 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 74: 248 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid ft (C) HEBRA: simple 5 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) ) NAME / KEY: other (B) LOCATION: 13 10 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 74: Pro Val Leu Asp Lys Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Ala 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 K (2) INFORMATION OF SEQ ID NO: 75: 20 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 25 (ii) ) TYPE OF MOLECULE: none 249 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 75: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Glu Leu Glu Ala (* 1 5 10 15 5 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 76: (i) CHARACTERISTICS OF THE SEQUENCE: 10 (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 15 (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 76: Pro Val Leu Asp Glu Phe Arg Glu Leu Leu Phe Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 25 20 250 (2) INFORMATION OF SEQ ID NO: 77: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple, (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 77: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Lys Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 78: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 251 (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 78: Pro Val Leu Asp Glu Phe Arg Asp Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 79: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 79: Pro Val Leu Asp Glu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 252 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 80: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none [xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 80: Pro Val Leu Asp Leu Phe Glu Arg Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 81: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 253 (ix) PECULIARITY: (A) NAME / KEY: other (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 81: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Trp Xaa Leu Glu Ala 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 / (2) INFORMATION OF SEQ ID NO: 82: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 11 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 82: 254 Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Ala Leu Lys 1 5 10 15 Gln Lys Leu Lys tí 20 5 (2) INFORMATION OF SEQ ID NO: 83: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 10 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 15 (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 83: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Ma 1 5 10 15 Leu Trp Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 84: 255 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (• '(C) HEBRA: simple 5 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 84: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 85: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 amino acids (B) TYPE: amino acid P (C) HEBRA: simple 20 (D) TOPOLOGY: linear (ii) ) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 85: 256 Pro Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Ala Leu 1 5 10 15 Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 86: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 86: Pro Val Leu Glu Leu Phe Glu Arg Leu Leu Asp Glu Leu Leu Asn Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 87: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 257 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: < «(A) NAME / KEY: others (B) LOCATION: 1 ... 22 (D) OTHER INFORMATION: all amino acids are in configuration D (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 87: 10 Pro Leu Leu Glu Leu Leu Lys Glu Leu Leu Gln Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 15 (2) INFORMATION ABOUT THE SEQ ID NO: 88: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids P (B) TYPE: amino acid 20 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) ) PECULIARITY: (A) NAME / KEY: other 25 (B) LOCATION: 13 258 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 88: Pro Val Leu Asp Lys Phe Arg Glu Leu Leu Asn Glu Xaa Leu Glu Ma 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 89: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 89: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Trp Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 259 (2) INFORMATION OF SEQ ID NO: 90: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 amino acids («(B) TYPE: amino acid 5 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) ) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 10 (B) LOCATION: 10 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 90: Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Ala Leu Lys Gln 1 5 10 15 Lys Leu Lys fr (2) INFORMATION OF SEQ ID NO: 91: 20 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 25 (ii) ) TYPE OF MOLECULE: none 260 (ix) PECULIARITY: (A) NAME / KEY: other (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 91: Pro Val Leu Asp Glu Phe Arg Glu Leu Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 92: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 92: 261 Pro Val Leu Asp Glu Phe Arg Glu Leu Tyr Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys tí 20 5 (2) INFORMATION OF SEQ ID NO: 93: (i) CHARACTERISTICS OF THE SEQUENCE: ( A) LENGTH: 22 amino acids (B) TYPE: amino acid 10 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 15 (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 93: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Lys Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 94: 262 (i) CHARACTERISTICS OF THE SEQUENCE: • (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 94: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Ala Leu Glu Ala 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 95: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib 263 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 95: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Leu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 96: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 22 (D) OTHER INFORMATION: all encoded amino acids are in configuration D (A) NAME / KEY: other (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib 264 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 96: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Xaa Leu Glu Ala G. # > 1 5 10 15 5 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 97: (i) CHARACTERISTICS OF THE SEQUENCE: 10 (A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) HEB &A: simple (D) TOPOLOGY: linear (ii) ) TYPE OF MOLECULE: none 15 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 97 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu 1 5 10 15 20 (2) INFORMATION OF SEQ ID NO: 98: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 25 (C) HEBRA: simple 265 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none fc (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 98: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Glu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 10 (2) INFORMATION OF SEQ ID NO: 99: (i) CHARACTERISTICS OF THE SEQUENCE: (A ) LENGTH: 22 amino acids (B) TYPE: amino acid 15 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 99; 20 Lys Leu Lys Gln Lys Leu Wing Glu Leu Leu Glu Asn Leu Leu Glu Arg 1 5 10 15 Phe Leu Asp Leu Val Pro 20 25 266 (2) INFORMATION OF SEQ ID NO: 100: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 22 (D) OTHER INFORMATION: all amino acids are / in configuration D (xi) DESCRIPTION OF THE SEQUENCE: SEQ TD NO: 100: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Lue Glu Ala 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 101: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 267 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 81: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Trp Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 102: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 102: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Leu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Glu Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 103: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 103: Pro Val Leu Asp Glu Phe Arg Glu Leu Leu Asn Glu Glu Leu Glu Ma 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 104: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 15 amino acids 269 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 104: Pro Leu Leu Asn Glu Leu Leu Glu Ala Leu Lys Gln Lys Leu Lys 1 5 10 15 (2) INFORMATION OF SEQ ID NO: 105: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 105: Pro Ma Ma Asp Wing Phe Arg Glu Wing Wing Asn Glu Wing Wing Glu Wing 1 5 10 15 Wing Lys Gln Lys Wing Lys 20 270 INFORMATION OF SEQ ID NO: 106: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 106; Pro Val Leu Asp Leu Phe Arg Glu Lys Leu Asn Glu Glu Leu Glu Ma 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 107: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 22 271 (D) OTHER INFORMATION: all amino acids are in configuration D (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 107: Lys Leu Lys Gln Lys Leu Wing Glu Leu Leu Glu Asn Lue Leu Glu Arg 1 5 10 15 Phe Leu Asp Leu Val Pro 20 (2) INFORMATION OF SEQ ID NO: 108: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 108: 272 Pro Val Leu Asp Leu Phe Arg Trp Leu Leu Asn Glu Xaa Leu Glu Wing 1 5 10 '15 Leu Lys Gln Lys Leu Lys ß 20 5 (2) INFORMATION OF SEQ ID NO: 109: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 10 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 109: 15 Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Arg Leu Glu Ma 1 5 10 15 Leu Lys Gln Lys Lys L »20 20 (2) INFORMATION SEQ ID NO: 110: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 25 (C) HEBRA: simple 273 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 5 (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (A) NAME / KEY: other (B) LOCATION: 14 10 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 110: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Xaa Glu Ala 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 111: 20 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 25 (ii) TYPE OF MOLECULE: none 274 (ix) PECULIARITY: (A) NAME / KEY: other (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 111: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Trp Glu Xaa Trp Glu Ala 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 112: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 112: 275 Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Ser Glu Ala 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 113: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 113: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Pro Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 114: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 276 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 114: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Met Glu Ala 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 115: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib 277 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 115: Pro Lys Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 116: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 116: Pro His Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Ma 1 5 10 15 Leu Lys Gln Lys Leu Lys. 20 (2) INFORMATION OF SEQ ID NO: 117: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 117: Pro Glu Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 118: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 279 (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 13 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 118: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Xaa Leu Glu Wing 1 5 10 15 Leu Glu Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 119: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 17 (D) OTHER INFORMATION: Xaa = Aib 280 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 119: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Glu Leu Glu Ala tí 1 5 10 15 5 Xaa Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 120: (i) CHARACTERISTICS OF THE SEQUENCE: 10 (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 15 (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 16 (D) OTHER INFORMATION: Xaa = Aib (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 120: Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Glu Leu Glu Xaa 1 5 10 15 Leu Lys Gln Lys Leu Lys 25 20 281 (2) INFORMATION OF SEQ ID NO: 121: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 121 Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Glu Leu Glu Wing 10 15 Leu Trp Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 122: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 122 282 Pro Val Leu Asp Glu Phe Arg Glu Lys Leu Asn Glu Glu Leu Glu Trp 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMACTION OF SEQ ID NO: 123: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 123: Gln Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 124: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 283 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 18 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: others (B) LOCATION: 20 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: other (B) LOCATION: 22 (D) OTHER INFORMATION: Xaa = Orn (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 124 Pro Val Leu Asp Leu Phe Xaa Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Xaa Gln Xaa Leu Xaa 20 (2) INFORMATION OF SEQ ID NO: 125: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids 284 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 125: Asn Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 126: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 126: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Gly Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 285 (2) INFORMATION OF SEQ ID NO: 127: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 127 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Leu 1 5 10 15 i Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 128: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 128 286 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Phe 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 129: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 129: Pro Val Leu Glu Leu Phe Asn Asu Leu Leu Arg Glu Leu Leu Glu Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 130: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 287 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none i (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 130: 5 Pro Val Leu Glu Leu Phe Asn Asp Leu Leu Arg Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 10 (2) INFORMATION FROM THE SEQ ID NO: 131: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 15 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 131: 20 Pro Val Leu Glu Leu Phe Lys Glu Leu Leu Asn Glu Leu Leu Asp Wing 1 5 '10 15 Leu Arg Gln Lys Leu Lys 20 25 288 INFORMATION OF SEQ ID NO: 132: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: any (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 132 10 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Asn Leu Leu Glu Wing 10 15 Leu Gln Lys Lys Leu Lys 20 15 (2) INFORMATION OF SEQ ID NO: 133: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids - (B) TYPE: amino acid 20 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none Xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 133: 25 289 Pro Val Leu Glu Leu Phe Glu Arg Leu Leu Glu Asp Leu Leu Gln Wing 1 5 10 15 Leu Asn Lys Lys Leu Lys tí 20 5 (2) INFORMATION OF SEQ ID NO: 134: (i) CHARACTERISTICS OF THE SEQUENCE: ( A) LENGTH: 22 amino acids (B) TYPE: amino acid 10 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 134: 15 Pro Val Leu Glu Leu Phe Glu Arg Leu Leu Glu Asp Leu Leu Lys Wing 1 5 10 15 Leu Asn Gln Lys Leu Lys 20 20 (2) INFORMATION ABOUT THE SEQ ID NO: 135: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 25 (C) HEBRA: simple 290 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 135: Asp Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 136: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 136: Pro Ala Leu Glu Leu Phe Lys Asp Leu Leu Gln Glu Leu Leu Glu Ala 1, 5 10 15 Leu Lys Gln Lys Leu Lys 20 291 (2) INFORMATION OF SEQ ID NO: 137: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 amino acids < _ *; (B) TYPE: amino acid 5 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 10 (B) LOCATION: 17 (D) OTHER INFORMATION: Xaa = naphthylalanine (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 137: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Gly Leu Glu Wing 1 5 10 15 Xaa Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 138: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 25 (D) TOPOLOGY: linear 292 (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 138: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Gly Leu Glu Trp 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 139: - (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 139: Pro Val Leu Asp Leu Phe Arg Glu Leu Trp Asn Glu Gly Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 140: (i) CHARACTERISTICS OF THE SEQUENCE: 293 (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple tí (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 18 (D) OTHER INFORMATION: Xaa = Orn 10 (A) NAME / KEY: others (B) LOCATION: 20 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: other (B) LOCATION: 22 (D) OTHER INFORMATION: Xaa = Orn (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 140: 20 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Gly Leu Glu Wing 1 5 10 15 Leu Xaa Gln Xaa Leu Xaa 20 25 294 (2) INFORMATION OF SEQ ID NO: 141: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 141 Pro Val Leu Asp Phe Phe Arg Glu Leu Leu Asn Glu Gly Leu Glu Wing 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 142: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 142 295 Pro Val Leu Glu Leu Phe Arg Glu Leu Leu Asn Glu Gly Leu Glu Wing 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 143: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 22 (D) OTHER INFORMATION: acetylated peptide in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 143: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Gly Leu Glu Ma 1 5 10 15 Leu Lys Gln Lys Leu Lys 20 296 (2) INFORMATION OF SEQ ID NO: 144: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa = D-Pro (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 144: Xaa Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Ma 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 145: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 297 (ii) TYPE OF MOLECULE: none • v (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 145: _ Gly Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Wing 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 146: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 15 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 146: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 147: 298 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 147: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Phe Asp Wing 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 148: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 148: '299 Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Gly Asp Ma 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 149: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 149: Pro Val Leu Glu Leu Phe Glu Asn Leu Trp Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 150: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 300 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none V (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 150: 5 Pro Leu Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 10 (2) INFORMATION FROM THE SEQ ID NO: 151: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 15 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 151: 20 Pro Val Leu Glu Leu Phe Glu Asn Leu Gly Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 25 301 (2) INFORMATION OF SEQ ID NO: 152: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 152 Pro Val Phe Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 / Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 153: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none [xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 153: 302 Wing Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Wing 1 5 10 15 Leu Gln Lys Lys Leu Lys tí 20 5 (2) INFORMATION OF SEQ ID NO: 154: (i) CHARACTERISTICS OF THE SEQUENCE: ( A) LENGTH: 22 amino acids (B) TYPE: amino acid 10 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 154: 15 Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Gly Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 20 (2) INFORMATION ABOUT THE SEQ ID NO: 155: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 25 (C) HEBRA: simple 303 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 155: Pro Val Leu Glu Leu Phe Leu Asn Leu Trp Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 156: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 156: Pro Val Leu Glu Leu Phe Leu Asn Leu Leu Glu Arg Leu Leu Asp Ma 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 304 (2) INFORMATION OF SEQ ID NO: 157: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids ti (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 157 10 Pro Val Leu Glu Phe Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Wing 10 15 Leu Gln Lys Lys Leu Lys 20 15 (2) INFORMATION OF SEQ ID NO: 158: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 20 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none ! xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 158: 25 305 Pro Val Leu Glu Leu Phe Leu Asn Leu Leu Glu Arg Leu Leu Asp Trp 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 159: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 159: Pro Val Leu Asp Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Wing 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 160: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY : linear 306 (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 160: - Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Trp 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 161: 10 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 15 (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 161: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Glu Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 162: 25 (i) CHARACTERISTICS OF THE SEQUENCE: 307 (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 162: Pro Val Leu Glu Leu Phe Glu Asn Trp Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 163: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 163: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Trp Asp Ala 1 5 10 15 308 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 164: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 164 Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Trp Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 165: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 309 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 165: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Leu 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 166: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 166: Pro Val Leu Glu Leu Phe Leu Asn Leu Leu Glu Lys Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 167: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids 310 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 167: Pro Val Leu Glu Leu Phe Glu Asn Gly Leu Glu Arg Leu Lase Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 168: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 168: Pro Val Leu Glu Leu Phe Glu Gln Leu Leu Glu Lys Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 311 (2) INFORMATION OF SEQ ID NO: 169: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 169: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Lys Leu Leu Asp Wing 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMACTION OF SEQ ID NO: 170: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 12 312 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: others (B) LOCATION: 19 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: others (B) LOCATION: 20 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: other (B) LOCATION: 22 (D) OTHER INFORMATION: Xaa = Orn (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 170: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Xaa Leu Leu Asp Ala 1 5 10 15 Leu Gln Xaa Xaa Leu Xaa 20 (2) INFORMATION OF SEQ ID NO: 171: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 313 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 171: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Lys Leu Leu Asp Leu 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 172: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 172: Pro Val Leu Glu Leu Phe Leu Asn Leu Leu Glu Arg Leu Gly Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 314 (2) INFORMATION OF SEQ ID NO: 173: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 173: Pro Val Leu Asp Leu Phe Asp Asn Leu Leu Asp Arg Leu Leu Asp Leu 10 15 Leu Asn Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 174: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 22 315 (D) OTHER INFORMATION: all amino acids are in configuration D (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 174: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 175: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 175: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Glu Leu 1 5 10 15 Leu Asn Lys Lys Leu Lys 20 316 INFORMATION OF SEQ ID NO: 176: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: any (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 176: 10 Pro Val Leu Glu Leu Trp Glu Asn Leu Leu Glu Arg Leu Leu Asp Wing 10 15 Leu Gln Lys Lys Leu Lys 20 15 (2) INFORMATION OF SEQ ID NO : 177: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 20 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 177: 317 Gly Val Leu Glu Leu Phe Leu Asn Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 178: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 178: Pro Val Leu Glu Leu Phe Asp Asn Leu Leu Glu Lys Leu Leu Glu Wing 1 5 10 15 Leu Gln Lys Lys Leu Arg 20 (2) INFORMATION OF SEQ ID NO: 179: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 318 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 179: Pro Val Leu Glu Leu Phe Asp Asn Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 180: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 180: Pro Val Leu Glu Leu Phe Asp Asn Leu Leu Asp Lys Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 319 (2) INFORMATION OF SEQ ID NO: 181: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids i ", (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) ) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 181: 10 Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Trp Leu Asp Ma 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 15 (2) INFORMATION ABOUT THE SEQ ID NO: 182: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 20 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 182 25 320 Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Lys Leu Leu Glu Ma 1 5 10 15 Leu Gln Lys Lys Leu Lys < • 20 5 (2) INFORMATION OF SEQ ID NO: 183: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 10 (C) HEBRA: simple (D) TOPOLOGY: linear ( ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 183: 15 Pro Leu Leu Glu Leu Phe Glu Asn Leu Leu Glu Lys Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 20 (2) INFORMATION ABOUT THE SEQ ID NO: 184: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid 25 (C) HEBRA: simple 321 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 184: Pro Val Leu Glu Leu Phe Leu Asn Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Trp Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 185: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 19 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: other (B) LOCATION: 20 (D) OTHER INFORMATION: Xaa = Orn 322 (A) NAME / KEY: other (B) LOCATION: 22 (D) OTHER INFORMATION: Xaa = Orn (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 185: Pro Val Leu Glu Leu Phe Glu Gln Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 186: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 186: Pro Val Leu Glu Leu Phe Glu Gln Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 323 (2) INFORMATION OF SEQ ID NO: 187: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 187: Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Ma 10 15 Leu Asn Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 188: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 188 324 Pro Val Leu Glu Leu Phe Glu Asn Leu Leu Asp Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 189: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 189: Asp Val Leu Glu Leu Phe Glu Asn Leu Leu Glu Arg Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Lys 20 (2) INFORMATION OF SEQ ID NO: 190: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) HEBRA: simple 325 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 190: Pro Val Leu Glu Phe Trp Asp Asn Leu Leu Asp Lys Leu Leu Asp Ala 1 5 10 15 Leu Gln Lys Lys Leu Arg 20 (2) INFORMATION OF SEQ ID NO: 191: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 191: 326 Pro Val Leu Asp Leu Leu Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 192: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 192: Pro Val Leu Asp Leu Phe Lys Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 193: (i) CHARACTERISTICS OF THE SEQUENCE: 327 (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION : 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 193 / Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 194: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: 328 (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 194: Pro Val Leu Glu Leu Phe Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 195: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 195: 329 Pro Val Leu 'Glu Leu Phe Lys Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 196: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 196: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Lys Asn Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 197: (i) CHARACTERISTICS OF THE SEQUENCE: 330 (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple tí (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: 1 ... 18 (D) OTHER INFORMATION: acetylated at the N-terminal and amidated at C-terminal 10 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 197: Pro Leu Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys. 1 5 10 15 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 198: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids 20 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: 25 (A) NAME / KEY: others 331 (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 198: Gly Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys 10 (2) INFORMATION OF SEQ ID NO: 199: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid 15 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 20 (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 199: 25 332 Pro Val Leu Asp Leu Phe Arg Glu Leu Trp Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 200: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 200: Asn Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 201: (i) CHARACTERISTICS OF THE SEQUENCE: 333 (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION : 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 201 Pro Leu Leu Asp Leu Phe Lys Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 202: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: 334 (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 202: Pro Ala Leu Glu Leu Phe Lys Asp Leu Leu Glu Glu Leu Arg Gln Lys 1 5 10 15 Leu Arg (2) INFORMATION OF SEQ ID NO: 203: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 203: 335 Wing Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 204: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 204: Pro Val Leu Asp Phe Phe Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 205: (i) CHARACTERISTICS OF THE SEQUENCE: 336 (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION : 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 205: Pro Val Leu Asp Leu Phe Arg Glu Trp Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 206: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: 337 (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 206: Pro Leu Leu Glu Leu Leu Lys Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 207: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 207: 338 Pro Val Leu Glu Leu Leu Lys Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 208: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 208: Pro Ala Leu Glu Leu Phe Lys Asp Leu Leu Glu Glu Leu Arg Gln Arg 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 209: (i) CHARACTERISTICS OF THE SEQUENCE: 339 (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 209: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Leu Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 210: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 210: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys 340 (2) INFORMATION OF SEQ ID NO: 211: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid 5 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 10 (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal / (A) NAME / KEY: other 15 (B) LOCATION: 14 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: other (B) LOCATION: 16 20 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: other (B) LOCATION: 18 (D) OTHER INFORMATION: Xaa = Orn 25 341 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 211: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Xaa Gln Xaa 1 5 10 15 Leu Xaa (2) INFORMATION OF SEQ ID NO: 121: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (A) NAME / KEY: other (B) LOCATION: 7 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: other (B) LOCATION: 14 342 (D) OTHER INFORMATION: Xaa = Orn (A) NAME / KEY: other __ (B) LOCATION: 16 (D) OTHER INFORMATION: Xaa = Orn (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 212: Pro Val Leu Asp Leu Phe Xaa Glu Leu Leu Glu Glu Leu Xaa Gln Xaa 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 213: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N-terminal and amidated in the C-terminal 343 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 213: Pro Ala Leu Glu Leu Phe Lys Asp Leu Leu Glu Glu Phe Arg Gln Arg 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 214: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (A) NAME / KEY: other (B) LOCATION: 1 (D) OTHER INFORMATION: Pro D configuration (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 214 344 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 215: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 215: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Trp Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 216: (i) CHARACTERISTICS OF THE SEQUENCE: 345 (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 216: Pro Val Leu Glu Leu Phe Lys Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 217: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 217 Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Leu Leu Lys Gln Lys 1 5 10 15 Leu Lys 346 (2) INFORMATION OF SEQ ID NO: 218: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 218: pro val leu asp leu phe arg glu leu leu asn glu leu leu gln lys 1 5 10 15 leu lys (2) INFORMATION OF SEQ ID NO: 219: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 347 (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 219: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Trp Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 220: (i) CHARACTERISTICS OF THE SECUENCTA: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 220: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Gln Lys Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 221: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids 348 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear tí (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated at the N-terminal and amidated at C-terminal 10 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 221: Asp Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 222: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids 20 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 222: 349 Pro Val Leu Asp Ma Phe Arg Glu Leu Leu Glu Ala Leu Leu Gln Leu 1 5 10 15 Lys Lys (2) INFORMATION OF SEQ ID NO: 223: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 223: Pro Val Leu Asp Wing Phe Arg Glu Leu Leu Glu Wing Leu Wing Gln * Leu 1 5 10 15 Lys Lys (2) INFORMATION OF SEQ ID NO: 224: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 350(xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 224: Pro Val Leu Asp Leu Phe Arg Glu Gly Trp Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 225: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 225: Pro Val Leu Asp Wing Phe Arg Glu Leu Wing Glu Wing Leu Wing Gln Leu 1 5 10 15 Lys Lys (2) INFORMATION OF SEQ ID NO: 226: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple 351 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 226: Pro Val Leu Asp Ma Phe Arg Glu Leu Gly Glu Ala Leu Leu Gln Leu 1 5 10 15 Lys Lys (2) INFORMATION OF SEQ ID NO: 227: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 227: 352 Pro Val Leu Asp Leu Phe Arg Glu Leu Gly Glu .Glu Leu Lys Gln Lys 1 5 10 - 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 228: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 228: Pro Val Leu Asp Leu Phe Arg Glu Gly Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 229: (i) CHARACTERISTICS OF THE SEQUENCE: 353 (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION : 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 229: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Glu Gly Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 230: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 354 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 230: Pro Val Leu Glu Leu Phe Glu Arg Leu Leu Glu Asp Leu Gln Lys Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 231: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 231: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Lys Leu Glu Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 232: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 355 (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 232: Pro Leu Leu Glu Leu Phe Lys Glu Leu Leu Glu Glu Leu Lys Gln Lys 1 5 10 15 Leu Lys (2) INFORMATION OF SEQ ID NO: 233: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: (B) TYPE: (C) HEBRA: (D) TOPOLOGY: (ii) TYPE OF MOLECULE: (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 202: this sequence was intentionally ignored (2) INFORMATION OF SEQ ID NO: 234: 356 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: (B) TYPE: (C) HEBRA: (D ~ T TOPOLOGY: (ii) TYPE OF MOLECULE: (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 234: This sequence was intentionally ignored (2) INFORMATION OF SEQ ID NO: 235: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: (B) TYPE: (C) HEBRA: (D) TOPOLOGY: (ii) TYPE OF MOLECULE: (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 235: this sequence was intentionally ignored (2) INFORMATION OF SEQ ID NO: 236: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: (B) TYPE: 357 (C) HEBRA: (D) TOPOLOGY: (ii) TYPE OF MOLECULE: (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 236: This sequence was intentionally ignored (2) INFORMATION OF SEQ ID NO: 237: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 237 Leu Asp Asp Leu Leu Gln Lys Trp Wing Glu Wing Phe Asn Gln Leu Leu 1 5 10 15 Lys Lys (2) INFORMATION OF SEQ ID NO: 238: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid 358 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (APNOMBRE / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 238: Glu Trp Leu Lys Ma Phe Tyr Glu Lys Val Leu Glu Lys Leu Lys Glu 1 5 10 15 Leu Phe (2) INFORMATION OF SEQ ID NO: 239: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 359 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 239: Glu Trp Leu Glu Ma Phe Tyr Lys Lys Val Leu Glu Lys Leu Lys Glu 1 5 10 15 Leu Phe (2) INFORMATION OF SEQ ID NO: 240: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 240: 360 Asp Trp Leu Lys Wing Phe Tyr Asp Lys Val Wing Glu Lys Leu Lys Glu 1 5 10 15 Wing Phe (2) INFORMATION OF SEQ ID NO: 241: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 241: Asp Trp Phe Lys Wing Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu 1 5 10 15 Phe Phe (2) INFORMATION OF SEQ ID NO: 242: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 361 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 242: Gly He Lys Lys Phe Leu Gly Ser He Trp Lys Phe He Lys Wing Phe 1 5 10 15 Val Gly - ~ (2) INFORMATION OF SEQ ID NO: 243: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TI PO: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 243: Asp Trp Phe Lys Wing Phe Tyr Asp Lys Val Wing Glu Lys Phe Lys Glu 1 5 10 15 Wing Phe (2) INFORMATION OF SEQ ID NO: 244: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 362 (ii) TYPE OF MOLECULE: none * (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 244: Asp Trp Leu Eys Wing Phe Tyr Asp Lys Val Wing Glu Lys Leu Lys Glu 1 5 10 15 Wing Phe (2) INFORMATION OF SEQ ID NO: 245: 10 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 15 (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 245: Asp Trp Leu Lys Wing Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu 1 5 10 15 20 Phe Phe (2) INFORMATION OF SEQ ID NO: 246: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids 25 (B) TYPE: amino acid 363 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 246: Glu Trp Leu Glu Wing Phe Tyr Lys Lys Val Leu Glu Lys Leu Lys Glu 1 5 10 15 Leu Phe (2) INFORMATION OF SEQ ID NO: 247: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 247: sp Tr Phe Lys Wing Phe Tyr Asp Lys Phe Phe Glu Lys Phe Lys Glu 1 5 10 15 Phe Phe (2) INFORMATION OF SEQ ID NO: 24 and 364 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (Dp-TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 248: Glu Trp Leu Lys Wing Phe Tyr Glu Lys Val Leu Glu Lys Leu Lys Glu 1 5 10 15 Leu Phe (2) INFORMATION OF SEQ ID NO: 249: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal 365 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 249: Glu Trp Leu Lys Wing Glu Tyr Glu Lys Val Glu Glu Lys Leu Lys Glu t 1 5 10 15 5 Leu Phe "- (2) INFORMATION OF SEQ ID NO: 250: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids 10 (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: 15 (A) NAME / KEY: others (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 250: Glu Trp Leu Lys Wing Glu Tyr Glu Lys Val Leu Glu Lys Leu Lys Glu 1 5 10 15 Leu Phe 25 366 (2) INFORMATION OF SEQ ID NO: 251: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids ti (B) TYPE: amino acid 5 (C) -? EBRA: simple (D) TOPOLOGY: linear ( ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: other 10 (B) LOCATION: 1 ... 18 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal / (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 251: 15 Glu Trp Leu Lys Wing Phe Tyr Lys Lys Val Leu Glu Lys Leu Lys Glu 1 5 10 15 Leu Phe (2) INFORMATION OF SEQ ID NO: 252: 20 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear 25 (ii) TYPE OF MOLECULE: none 367 (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 15 (D) OTHER INFORMATION: acetylated in the N terminal and - ~ amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 252: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Gln Lys Leu Lys 1 5 10 15 (2) INFORMATION OF SEQ ID NO: 253: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 16 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 16 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 253: 368 pro val leu asp leu phe arg glu leu leu glu glu leu lys gln lys 1 5 10 15 (2) INFORMATION OF SEQ ID NO: 254: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 16 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 16 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 254: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Lys Leu Lys Gln Lys 1 5 10 15 (2) INFORMATION OF SEQ ID NO: 255: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 15 amino acids (B) TYPE: amino acid 369 (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) ~ NAME / KEY: others (B) LOCATION: 1 ... 15 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 255: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Glu Lys Leu Gln Lys 10 15 (2) INFORMATION OF SEQ ID NO: 256: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 16 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 16 (D) OTHER INFORMATION: acetylated in N-terminal and 370 amidado in the C terminal _ »V (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 256: i Pro Val Leu Asp- Leu Phe Arg Glu Leu Leu Glu Wing Leu Lys Gln Lys 1 5 10 15 (2) INFORMATION OF SEQ ID NO: 257: (i) CHARACTERISTICS OF THE SEQUENCE: 10 (A) LENGTH: 16 amino acids (B) TYPE: amino acid (C) HEBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none 15 (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 16 (D) OTHER INFORMATION: acetylated in N terminal and amidated in C terminal 20 (xi) DESCRI PECTION OF THE SEQUENCE: SEQ ID NO: 257: Pro Val Leu Asp Leu Phe Glu Asn Leu Leu Glu Arg Leu Lys Gln Lys 1 5 10 15 25 371 (2) INFORMATION OF SEQ ID NO: 258: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 16 amino acids (B) TYPE: amino acid (Cp? EBRA: simple (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: none (ix) PECULIARITY: (A) NAME / KEY: others (B) LOCATION: 1 ... 16 (D) OTHER INFORMATION: acetylated in the N terminal and amidated in the C terminal (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 258: Pro Val Leu Asp Leu Phe Arg Glu Leu Leu Asn Glu Leu Lys Gln Lys 1 5 10 15

Claims (55)

1. 372 CLAIMS 1. An ApoA-I agonist consisting of: (i) a peptide or peptide analogue of 15 to 29 residues which forms a helical antipathic in the presence of lipids and which consists of the structural formula (I): Z? -X? -X2-X3-X4 -5-6-X7 ~ 8-X9-Xl0-Xll-l2 ~ Xl3 ~ Xl4-Xl5-Xl6_Xl7"Xl8- Xl9- 20 ~ X21- 22-X23_Z2 or a pharmaceutically acceptable salt thereof, wherein: Xi is Pro (P), Wing (A), Gly (G), Gln (Q), Asn (N), Asp (D) or D-Pro (p), X2 is an aliphatic residue X3 is Leu (L) or Phe (F); X4 is Glu (E); Xs is an aliphatic residue; X7 is Glu (E) or Leu (L); Xa is Asn (N) or Gln (Q); Xg is Leu (L); Xio is Leu (L), Trp (W) or Gly (G); Xii is an acid residue; X12 is Arg (R); 373 X13 is Leu (L) or Gly (G); Xi4 is Leu (L), Phe (F) or Gly (G); X15 is Asp (D); Xi6 is Ala (A); X17 is JLeu (L); X19 is a basic residue; X20 is a basic waste; X21 is Leu (L); X22 is a basic residue; X23 is absent or is a basic waste; Zi is H2N- or RC (0) NH-; Z2 is -C (0) NRR, -C (O) OR or -C (0) OH or a salt thereof; each R is independently -H, C? -C6 alkyl. Ci-Cβ alkenyl, Ci-Cβ alkynyl; aryl (from C5-C20) t alkaryl from (C6-C26). 5 to 20 membered heteroaryl, 6 to 26 membered heteroaryl or a peptide or peptide analog of 1 to 7 residues; each "-" between residues Xn independently designates an amide bond, a substituted amide bond, an isoster of an amide or a mimetic amide; or (ii) a form with a deletion of the structural formula (I) in which at least one and up to eight of the residues Xi, X2, X3, X4, X5, X6, X7, X8, Xg, X10, Xll, Xl2 / Xl3 / Xl4 / Xl5 Xl6 / 374 i7 ^ Xi8 Xi9 20 X21 and X22 are subjected to deletion; or (iii) an altered form of the structural formula (I) in which at least one of the residues Xi, X2. X3r 4 / X5 / Xd, X7 / Xd X? f XlO Xll Xl2 i Xl3 / Xl4 > Xl5 / Xl ß? Xl7 / Xl8 Xl9 X20r X21? X22 -o. X23 is substituted conservatively with another residue.
2. 2. The ApoA-I agonist of claim 1 which exhibits at least about 38% activation activity of the LCAT compared to human ApoA-I.
3. 3. The ApoA-I agonist of claim 1 which is the altered form of the structural formula (I).
4. 4. The ApoA-I agonist of claim 3 wherein the hydrophobic residues are fixed according to structural formula (I) and at least one non-fixed residue is conservatively substituted with another residue. The ApoA-I agonist of claim 4, wherein: X1 is Pro (P), D-Pro (p), Gly (G), Asn (N) or Ala (A); X2 is Ala (A), Leu (L) or Val (V); X3 is Leu (L) or Phe (F); X5 is Leu (L); X6 is Phe (F); X9 is Leu (L); X10 is Leu (L), Trp (W) or Gly (G); X13 is Leu (L) or Gly (G); 375 Xi4 is Leu (L), Phe (F) or Gly (G); X17 is Leu (L); X21 is Leu (L); and when one of X4, X7, Xß, Xn, X12, X15. Xi8 > Xi9 / X22 or X23 is conservatively substituted with another residue. 6. The ApoA-I agonist of claim 3 in which the hydrophilic residues are fixed according to the structural formula (I) and at least one non-fixed residue is conservatively substituted with another residue. 7. The ApoA-I agonist of claim 6, wherein: X4 is Glu (E); X7 is Glu (E); X8 is Asn (N) or Gln (Q); Xn is Asp (D) or Glu (E); X12 is Arg (R); X15 is Asp (D); X19 is Lys (K); X20 is Lys (K); X22 is Lys (K); X23 is absent or is Lys (K); and at least one of Xi, X, X3, X5, Xd. X9 Xio ^ Xi3 ^ i4 / X16, Xi7 and? 20 is replaced conservatively with another 376 residue. 8. The ApoA-I agonist of claim 6 wherein X3 is Leu (L) or Phe (F), X6 is Phe (F), Xg is Leu (L),? 10 is Leu (L) or Trp (W) or Gly (G), and at least one of Xi, X2, X5, X3, Xi4. ^ _ I6. X17 and X21 are substituted conservatively with another residue. 9. The ApoA-I agonist of the claim 5 or 7 in which the substituent residue is classified within the same subcategory as the substituted residue. 10. The ApoA-I agonist of claim 1 which is the deletion form of structural formula (I). 11. The ApoA-I agonist of claim 10 wherein a helical turn of the peptide or peptide analog is subjected to deletion. 12. The ApoA-I agonist of claim 1 which is a peptide or peptide analog of 22-23 residues of the structural formula (I). 13. The ApoA-I agonist of claim 12, in which: the "-" between residues designates -C (0) NH-; Zi is H2N-; and Z2 is -C (0) OH or a salt thereof. The ApoA-I agonist of claim 13, wherein: Xi is Pro (P), Ala (A), Gly (G), Asn (N), Asp (D), Gln 377 (Q) or D-Pro (P. - X2 is Ala (A>, Val (V) or Leu (L);? 3 is Leu (L) or Phe (F); X4 is Glu (E 1 - Xs is Leu L -? 6 is Phe F - X is Leu L or Glu (G);? 8 is Asn N or Gln (Q); Xg is Leu L r Xio is Leu L, Trp (W) or Gly (G); Xn is Glu E Xl2 is Arg R - Xl3 is Leu L) or Gly (G); Xl4 is Leu L, Phe (F) or Gly (G); Xl5 is Asp (D) / Xl6 is Ala (A) / X17 is Leu (L) / Xl8 is Asn (N) or Gln (Q); Xig is Lys (K) / - X20 is Lys (K) - X21 is Leu (L) r X22 is Lys (K) • and X23 is absent or Lys (K) 15. The ApoA-I agonist of claim 14, wherein X23 is absent. 378 16. The ApoA-I agonist of claim 14, wherein each of Xio, X? 3 and Xi4 is different from Gly (G). 17. The ApoA-I agonist of claim 14, wherein each of Xio. X13 or X14 is Gly (G) and the others are different from Gly (G). 18. The ApoA-I agonist of claim 1, which is selected from the group consisting of: peptide 144 PVLELFENLLERLLDALQKKLK (SEQ ID NO: 144); peptide 145 GVLELFENLLERLLDALQKKLK (SEQ ID NO: 145); peptide 146 PVLELFENLLERLLDALQKKLK (SEQ ID NO: 146); peptide 147 PVLELFENLLERLFDALQKKLK (SEQ ID NO: 147); peptide 148: PVLELFENLLERLGDALQKKLK (SEQ ID NO: 148); peptide 149: PVLELFENLWERLLDALQKKLK (SEQ ID NO: 149); peptide 150: PLLELFENLLERLLDALQKKLK (SEQ ID NO: 150); peptide 151: PVLELFENLGERLLDALQKKLK (SEQ ID NO: 151); peptide 152: PVFELFENLLERLLDALQKRLK (SEQ ID NO: 152); peptide 153: AVLELFENLLERLLDALQKKLK (SEQ ID NO: 153); peptide 154: PVLELFENLLERGLDALQKKLK (SEQ ID NO: 154); peptide 155: PVLELFLNLWERLLDALQKKLK (SEQ ID NO: 155); peptide 186: PVLELFEQLLERLLDALQKKLK (SEQ ID NO: 186); peptide 187: PVLELFENLLERLLDALNKKLK (SEQ ID NO: 187); peptide 188: PVLELFENLLDRLLDALQKKLK (SEQ ID NO: 188); peptide 189: DVLELFENLLERLLDALQKKLK (SEQ ID NO: 189); and the acylated forms in the N-terminal and / or the amidated or esterified forms in the C-terminal thereof. 379 19. A multimeric ApoA-I agonist, which has at least about 38% activation activity of the LCAT compared to human ApoA-I and which has the structural formula (II): (II) HH- [LLm-HHJ n-LLm-HH or a pharmaceutically acceptable salt thereof, wherein: each m is independently an integer from 0 to 1; n is an integer from 0 to 10; each "HH" is independently a peptide or peptide analogue according to claim 1; each "LL" is independently a bifunctional linker; and each "-" independently designates a covalent bond. 20. A multimeric ApoA-I agonist, which has at least about 38% activation activity of LCAT compared to human ApoA-I and has the formula 20 structural (III): (III) X-Nya-X (ya_1) (Nyb-X (yb-i)) p or a pharmaceutically acceptable salt thereof, wherein: each X is independently HH- (LLm-HH) nLLm-HH; 25 each HH is independently a 380 core peptide structure (I) or an analogous or mutated form, truncated, with internal or extended deletion thereof as described herein; each LL is independently a bifunctional linker; each m is independently an integer from 0 to 1; each n is independently an integer from 0 to 8; Nya and Nyb are each independently a multifunctional link portion where Ya and b represent the number of functional groups in Nya and Nyb, respectively; each ya or and b is independently an integer from 3 to 8; p is an integer from 0 to 7; and each "-" independently designates a covalent bond. 21. A multimeric ApoA-I agonist, which has at least about 38% activation activity of the LCAT compared to human ApoA-I and which has the structural formula (IV) or (V): (IV) (V) 381 or a pharmaceutically acceptable salt thereof, wherein: each X is independently HH- (LLm-HH) nLLm-HH; each HH is independently a peptide or a peptide analogue according to claim 1; each LL is independently a bifunctional linker; Each n is independently an integer from 0 to 1 [sic]; Each m is independently an integer from 0 to 8 [sic]; R1 is -OR or -NRR; and each R is independently -H, Ci-Cg alkyl, Ci-Cβ alkenyl, C?-C6 alkynyl; (C5-C20) aryl (C6-C26) alkaryl-5 to 6-membered heteroaryl or 6-to-26-membered heteroaryl. 22. The ApoA-I multimeric agonist of claim 19, 20 or 21 wherein the bifunctional linker is cleavable. 23. The ApoA-I multimeric agonist of claim 19, 20 or 21 wherein n is 0. 24. The ApoA-I multimeric agonist of claim 22 wherein m is 0. 25. The multimeric agonist of ApoA-I of claim 19, 20 or 21 wherein each HH is independently a peptide according to claim 13. 26. The multimeric ApoA-I agonist of claim 19, 20 or 21 wherein each HH is independently a peptide according to claim 14. 382 27. The ApoA-I multimeric agonist of claim 19, 20 or 21 in which each HH is independently a peptide according to claim 18. t 28. An ApoA-I-lipid agonist complex consisting of an agonist of ApoA-I and a lipid, where the agonist ApoA-I is a peptide or peptide analogue according to claim 1, a multimeric ApoA-I agonist according to claim 19, a multimeric ApoA-I agonist according to claim 20 or a multimeric ApoA agonist 10. -I according to claim 21. 29. The ApoA-I-lipid agonist complex of claim 28 wherein the ApoA-I agonist is a peptide according to claim 12. 30. The ApoA agonist complex -I-lipid of claim 28 in which the ApoA-I agonist is a peptide according to claim 13. 31. The ApoA-I-lipid agonist complex of claim 28 in which the ApoA agonist -I is a peptide according to claim 14. 32. The ApoA-I-lipid agonist complex of claim 28 wherein the ApoA-I agonist is a peptide according to claim 18. 33. The ApoA-I-lipid agonist complex of claim 28 in which the lipid is sphingomyelin. 25 34. The ApoA-I-lipid agonist complex of 383 claim 28 which is in the form of a lyophilized powder. 35. The ApoA-I-lipid agonist complex of claim 28 which is in the form of a solution. 36. A pharmaceutical composition containing an ApoA-I agonist and a pharmaceutically acceptable carrier, excipient or diluent, wherein the ApoA-I agonist is a peptide or peptide analogue according to claim 1, is a multimeric ApoA agonist. -I according to claim 10, is a multimeric ApoA-I agonist according to claim 20 or a multimeric ApoA-I agonist according to claim 21. 37. The pharmaceutical composition of claim 36 wherein the ApoA-I agonist is a peptide according to claim 12. 38. The pharmaceutical composition of claim 36 wherein the ApoA-I agonist is a peptide in accordance with claim 13. 39. The pharmaceutical composition of claim 36 wherein the ApoA-I agonist is a peptide according to claim 14. 40. The pharmaceutical composition of claim 36 wherein the ApoA-I agonist is a peptide according to claim 18. 41. The pharmaceutical composition of claim 36, 384 37, 38, 39 or 40, in which the ApoA-I agonist is in the form of an ApoA-I-lipid agonist complex, the complex consisting of the ApoA-I agonist and a lipid. 42. The pharmaceutical composition of claim 41 in 5 which the ApoA-I-lipid agonist complex is in the form of a lyophilized powder. 43. A method of treatment of an individual suffering from an abnormality associated with dyslipidemia, the method is the step of administering to the individual an effective amount 10 of the ApoA-I agonist of claim 1. 44. The method of claim 43, wherein the ApoA-I agonist is in the form of a pharmaceutical composition, the composition containing the ApoA-I agonist and a carrier, excipient or diluent 15 pharmaceutically acceptable. 45. The method of claim 43 wherein the ApoA-I agonist is in the form of an ApoA-I-lipid agonist complex, the complex consisting of the ApoA-I agonist and a lipid. 46. The method of claim 43, wherein the abnormality associated with dyslipidemia is hypercholesterolemia. 47. The method of claim 43, wherein the abnormality associated with dyslipidemia is cardiovascular disease. 25 48. The method of claim -43, in which the 385 anomaly associated with dyslipidemia is atherosclerosis. 49. The method of claim 43, wherein the abnormality associated with dyslipidemia is restenosis. 50. The method of claim 43, wherein the abnormality associated with dyslipidemia is HDL deficiency or? ApoA-I. 51. The method of claim 43, wherein the abnormality associated with dyslipidemia is hypertriglyceridemia. 52. The method of claim 43, wherein the abnormality associated with dyslipidemia is metabolic syndrome. 53. A method for treating an individual suffering from septic shock, the method comprises the steps of administering to the individual an effective amount of the ApoA-I agonist of claim 1. 54. The method of claim 43 or 53 wherein the individual is a human. 55. The method of claim 43 or 53 wherein the individual is administered about 0.5 mg / kg to about 100 mg / kg of the ApoA-I agonist.