MXPA01004832A - Regulatory/unfolding peptides of ezrin - Google Patents

Abstract

This invention describes novel charged molecules which specifically bind to the Hepreceptor, a regulatory site which I have discovered in human ezrin. My invention is that when peptides or other charged molecules bind to the Hepreceptor, medically useful immune responses are induced. These charged molecules can be administered orally and by other routes for the treatment of various infectious diseases and cancer. I have determined that the Hepreceptor (human ezrin 308-373) comprises of two adjacent alpha helical domains which are folded together at a hinge region (M339-M340) and stabilised by complimentary side chain charges of the primary amino acid sequence in the soluble cytoplasmic conformation of ezrin. I have determined that in the unfolded membrane associated conformation of ezrin, the Hepreceptor is pushed through the cell membrane and is exposed on the outer surface of the cell. Hepreceptor-Domain A (amino acid numbers 308-339 of human ezrin), comprises of the following 32 amino acid sequence. SEQ ID 1 A R E E K H Q K Q L E R Q Q L E T E K K R R E T V E R E K E Q M Hepreceptor-Domain B (amino acid numbers 340-373 of human ezrin), comprises of the following 34 amino acid sequence (Tyrosine 353 [Y]may be phosphorylated to phosphotyrosine [Yp]in the membrane associated conformation of ezrin):SEQ ID 2 M R E K E E L M L R L Q D Y(p) E E K T K K A E R E L S E Q I Q R A L Q.

Description

PEPTIDES REGU ATORIOS / DESDOBORES DE EZRIN DESCRIPTION OF THE INVENTION The field of the present invention relates to the treatment of infectious diseases and cancer by inducing immune responses against the disease. The growing problem of new strains of pathogenic bacteria resistant to antibiotics, the limited range of effective compounds against chronic viral and fungal infections and the shortening of effective anti-cancer treatments demonstrates the need for compounds that can increase host defense against these medical problems. This invention relates to novel charged molecules that stimulate immune responses by binding to Hepreceptor, a novel active site in human ezrin that has been discovered herein. Ezrin is a member of the ERM family (ezrin-radixin-moesin) of proteins that play structural and regulatory roles in a wide range of cell types. There is considerable evidence to indicate that ezrin regulates the structure of the cortical cytoskeleton to control the topography of the cell surface. Ezrin adopts two main conformations: 1) a soluble bent form found in the cytoplasm and, 2) a split and elongated shape that are attached to the cytoplasmic surface of the cell membrane particularly together with the microvilli and other structural related to the activation. The domain of the N-terminus of the protein is bound to the cytoplasmic surface of the membrane while the part of the C-terminus is linked to the actin cytoskeleton. Ezrin is a substrate of tyrosine kinase in the T cells and is also phosphorylated tyrosine as a result of the stimulation of the Epidermal Growth Factor (EGF) of the EGF receptor. The domain of the N terminal of ezrin. in its extended conformation it binds to the cytoplasmic tail of CD44 in the presence of PIP2. Ezrin can also bind to the cytoplasmic tail of ICAM-2. Ezrin is very sensitive to regulatory proteases such as calpain and is rapidly rotated during cell activation. Anthony Bretscher, David Reczek and Mark Berryman (1997) "Ezrin: a protein requiring conformational activation to link microfilaments to the plasma membrane in the assembly of cell surface structures" Journal of Cell Science 110: 3011-3018. Detailed analysis of the secondary structure of ezrin shows that there are three major structural domains: an N terminal domain of amino acids 1 to 300, a highly charged alpha domain of amino acids 300 to 470 and the C terminal domain of amino acids 470 to 585. Structural modeling suggests that the alpha domain is doubled in two antiparallel helices in the soluble globular form of ezrin although the location of the hinge has not been identified. In the model of the extended forphorylated form, ezrin is bound to the inner surface of the cell membrane by the N-terminal domain, the alpha domains of two ezrin molecules are paired in antiparallel dimers and located below the surface membrane cell phone. In this extended form, ezrin is tyrosine phosphorylated on tyrosine 353 (Yp 353). Ossi Turunen, Markku Sainio, Juha Jaaskelainen, Olli Carpen, Antti Vaheri (1998) "Structure-Function relationships in the ezrin family and the effect of tumor-associated point mutations in neurofibromatosis 2 protein" Biochimica et Biophysica Acta 1387: 1-16. It has been described in U.S. Patent 5,773,573 that the fourteen amino acid peptide HEP1, (amino acid sequence of TEKKRRETEREKE, SEQ ID 28, identical to amino acids 324-337 of human ezrin) which has a 70% identity to the C terminal of gpl20 can inhibit HIV replication in vivo in man. At that time it is believed that the observed anti-HIV effect of the HEP1 peptide is due to HEP1 administered orally by inducing. TABLE 1 Amino acids, three-letter code, one-letter code and side chain loads LOADS IN SIDE CHAINS OF AMINO ACIDS IN pH PHYSIOLOGICAL Amino Acid Code of a Load Symbol three letters letter BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram of the alignments of the primary amino acid sequences of: a) the double antiparallel helices associated with the Hepreceptor in soluble ezrin. b) The unfolding helix of the Hepreceiver in membrane associated with ezrin with an example of a peptide ligand. c) Two split hepreceptors that form a dimer of antiparallel associated helices during an interaction between two cells. Figure 2 is an illustration of the relationship between the Hepreceptor in ezrin, its ligands, cell membranes, cell surface receptors and cytoskeletal components. BRIEF DESCRIPTION OF SEQUENCES SEQ ID 1 is an amino acid sequence of a peptide according to the present invention. SEQ ID 2 is an amino acid sequence of a peptide according to the present invention.

SEQ ID 3 is an amino acid sequence of a peptide according to the present invention. SEQ ID 4 is an amino acid sequence of a peptide according to the present invention. SEQ ID 5 is an amino acid sequence of a peptide according to the present invention. SEQ ID 6 is an amino acid sequence of a peptide according to the present invention. SEQ ID 7 is an amino acid sequence of a peptide according to the present invention. SEQ ID 8 is an amino acid sequence of a peptide according to the present invention. SEQ ID 9 is an amino acid sequence of a peptide according to the present invention. SEQ ID 10 is an amino acid sequence of a peptide according to the present invention. SEQ ID 11 is an amino acid sequence of a peptide according to the present invention. SEQ ID 12 is an amino acid sequence of a peptide according to the present invention. SEQ ID 13 is an amino acid sequence of a peptide according to the present invention. SEQ ID 14 is an amino acid sequence of a peptide according to the present invention.

SEQ ID 15 is an amino acid sequence of a peptide according to the present invention. SEQ ID 16 is an amino acid sequence of a peptide according to the present invention. SEQ ID 17 is an amino acid sequence of a peptide according to the present invention. SEQ ID 18 is an amino acid sequence of a peptide according to the present invention. SEQ ID 19 is an amino acid sequence of a peptide according to the present invention. SEQ ID 20 is an amino acid sequence of a peptide according to the present invention. SEQ ID 21 is an amino acid sequence of a peptide according to the present invention. SEQ ID 22 is an amino acid sequence of a peptide according to the present invention. SEQ ID 23 is an amino acid sequence of a peptide according to the present invention. SEQ ID 24 is an amino acid sequence of a peptide according to the present invention. SEQ ID 25 is an amino acid sequence of a peptide according to the present invention. SEQ ID 26 is an amino acid sequence of a peptide according to the present invention.

SEQ ID 27 is an amino acid sequence of a peptide according to the present invention. SEQ ID 28 is an amino acid sequence of a peptide according to the present invention. The soluble conformation of ezrin found in the cytoplasm comprises two adjacent helical alpha domains that are folded together in a hinge region (M339-M340) in two antiparallel helices stabilized by side chain charges complementary to the primary amino acid sequence. It is the object of this invention that the positively and negatively charged side chains of the amino acid sequence of Hepeceptor Domain A are complementary to the positively and negatively charged side chains of the amino acid sequence of Domain B of the Heprecipient. In the activated open conformation of ezrin, the interaction of Domain A and Domain B of the Hepreceptors of two different ezrin molecules allows the formation of antiparallel dimers. In addition to antiparallel ezrin dimers that form below the cell surface, it is determined herein that these dimers can be formed between a Hepreceptor exposed on the surface in a cell with a Hepreceptor exposed on the surface of another cell. When the two Hepreceptors make contact during close association of two cell surfaces, an activation signal is initiated in both cells (Figure 2). Any charged molecule that partially mimics the interaction between the side chain loads of Domain A and Domain B of the Hepreceptors will give rise to a medically useful biological response. Domain A of the Heprecipient (amino acid numbers 308-339 of human ezrin) comprises the following sequence of 32 amino acids. (Sequences are listed using the one letter code for each amino acid written from terminal N to terminal C of the polypeptide Yp represents the form of phosphotyrosine found in vivo). SEQ ID 1 AREEKHQKQLERQQLETEKKR RETVEREKEQM In U.S. Patent 5,773,573, the anti-HIV activity of the HEPl peptide (SEQ ID 28) which has now been discovered has a sequence identical to the part of the A domain of the heprecipient (amino acid expansion) is described. 324-337 of the human ezrin sequence). In the above patent the presumption is made that the anti-HIV activity is due to the induction of immunological tolerance to autoreactive immune responses induced by the HIV C-terminal gpl20. Now it can be discovered that the anti-HIV activity of HEPl is due to its binding to Hepatitis B Domain and the induction of a novel immune response. It is an object of this invention that finds novedqs peptides derived from the ezrin Hepreceptor with activity significantly superior to HEPl. The B domain of the Hepreceptor (amino acid numbers 340-373 of human ezrin), comprises of the following sequence of 34 amino acids (Tyrosine 353 [Y] can be phosphorylated to phosphotyrosine [Yp] in the membrane associated with the ezrin conformation): SEQ ID 2 MREKEELMLRLQDY (p, EEKTKKAERELSEQIQRALQ It has been determined herein that Domain B of the Hepreceptor is the site in ezrin to which HIV gpl20 binds during brain infection. (HIV gpl20 binds to Domain B of the Heprecipient using its amino acids from the loaded C-terminus that has a 70% identity to the Hepreceiver A Domain part.) Novel charged molecules that bind to the Hepreceptor may be useful in treating HIV-related dementia Claudia Hecker, Christoph eise, Jurgen Schneider-Schaulies, Harvey Holmes, Volker ter Meulen (1997) "Specific binding of HIV-1 envelope protein gpl20 to the structural membrane proteins ezrin and moesin" Virus Research 4 9 215-223. It is demonstrated in the present (EXAMPLE IA) that the Hepreceptor peptides have significant adjuvant activity and this is demonstrated by increasing the IgG antibody response to Ovalbumin in mice using HEPl, Rupe312, Rupel014, Rupel024 and Rupe2032. I have also demonstrated in the present (EXAMPLE IB) the activity of the Heprecipient peptides in increasing the antibody-dependent cytotoxic response in Timo for sheep red cells (CRB) in mice using HEPl, Rupe312, Rupel5, Rupel014, Rupel024 and Rupe2032. (Rupe312 SEQ ID 8: KKRRETVERE and Rupel5 SEQ ID 3: TEKKR and Rupe 1014 SEQ ID 16: EREKE and Rupel024 SEQ ID 17: EREKEQMMREKEEL and Rupe2032 SEQ ID 19: KEELMLRLQDYEE and HEPl SEQ ID 28: TEKKRRETVEREKE). It has been demonstrated in the present (EXAMPLE 2) that Hepreceptor peptides have significant antitumor activity and this is demonstrated by Hepreceptor peptides reducing the growth rate of rapidly growing transplanted sarcomas and transplanted cervical cancer of lower growth in mice using Rupe312 and Rupe414. (Rupe312 SEQ ID 8: KKRRETVERE and Rupe414 SEQ ID 13: KRRETVEREKE). It has been demonstrated in the present (EXAMPLE 3) that HEPl therapy (10 mg per day orally for either thirty days or ninety days) in 21 HIV-infected patients induces immune responses leading to clinical improvement over the following six months after of therapy, as measured by increasing the population of CD4 T lymphocytes and declining opportunistic infections, declining infectivity to HIV and declining CD38 CD8 population of T lymphocytes (an established prognostic marker of AIDS progression). M Levancher, F Hulstaert, s. Tallet, S Ullery, J J Pocidalo, B A Bach (1992) "The significance of activation markers on CD8 lymphocytes in human imdeficiency syndrome: staging and prognostic value" Clinical Experimental Immunology 90 376-382. An average increase in the level of expression of CD44 and MHC Class I in T lymphocytes is observed during six months which seems to correlate also with the clinical improvement. No toxicity is detected with the administration of HEPl. Increases in MHC Class I expression and CD44 expression are associated with increases in T cell memory and Class I restricted cell-mediated immunity. Stephan Oehen and Karin Brduscha-Riem (1998) "Differentiation of Na? Ve CTL to Effector and Memory CTL: Correlation of Effector Function with Phenotype and Cell Division" The Journal of Immunology 161 5338-5346. The results of this test show that a peptide or other charged molecule that mimics all or part of the Hepreceptor can give rise to an activation signal that eventually leads to a change in the homeostasis of the immune system and long-term regulation of humoral and mediated by cell. It has also been shown herein that acute and chronic candida infection in women can be treated and cured by the immune response that originates from the Hepreceptor stimulation (EXAMPLE 4). It has been demonstrated herein that peptides derived from the Hepreceptor can activate monocytes and macrophages in mice both in vitro and in vivo, which results in a protective immune response (EXAMPLE 5). The peptides of this invention have significantly higher activity than HEPl. Hepreceptor stimulation also leads to the activation of human peripheral blood mononuclear cells, which is demonstrated by measuring the incorporation of radioactive tritiated thymidine into the DNA of the growing cells. The novel peptides, Rupe312 and Rupe414 derived from the form of Domain A of the Heprecipsor have an activity ten times higher than HEPl. (EXAMPLE 6). (Rupe312 SEQ ID 8: KKRRETVERE and Rupe414 SEQ ID 13: KRRETVEREKE). It has also been discovered herein that a 24-hour incubation of white cell corpuscles (CCB) with peptides derived from the Hepreceptor result in a fall in the cell surface expression of MHC Class I, probably due to cellular activation and internationalization of the receptor, and an increase in the total population of macrophages expressing MHC Class I. This is consistent with the long-term increase in the population cells expressing MHC Class I observed in patients with HIV during the six months following HEPl therapy. In this test system Rupe312 and Rupe414 have significantly higher activity than HEPl) (EXAMPLE 7). (Rupe312 SEQ ID 8: KKRRETVERE and Rupe414 SEQ ID 13: KRRETVEREKE). It has been demonstrated in the present (EXAMPLE 8) that Hepreceptor peptides have significant suppressive effect on the expression of IL-8. Inhibition of IL-8 may play a role in the selective activity of Hepreceptor peptides in activating monocytes / macrophages. (Rupe312 SEQ ID 8: KKRRETVERE). It has been demonstrated in the present (EXAMPLE 8) that the Hepreceptor peptides (1-100 nanograms / mouse) protect the mice from acute infection by Salmonella Tryphimurium. (Rupel5 SEQ ID 3: TEKKR and Rupel024 SEQ ID 17: EREKEQMMREKEEL and HEPl SEQ ID 28: TEKKRRETVEREKE). It has been demonstrated in the present (EXAMPLE 10) that a very low dose of Hepreceptor peptides (1-1000 nanograms / mouse) increase the survival time in a lethal herpesvirus infection model in mouse.

(HEPl SEQ ID 28: TEKKRRETVEREKE). This invention describes charged molecules that specifically bind to the Hepreceptor. Three groups of novel charged peptides having identical sequences to the amino acid sequences of the complementary Hepreciptor domains and which bind either to Header B Domain (SEQ ID 3 - SEQ ID 16), or both, have been designated herein. Domain A and B (SEQ ID 17), or that link to Domain A (SEQ ID 18 - SEQ ID 27). The peptides that are an object of this invention are probably linked to Hepreceptors exposed to cell surface and stabilize the split conformation of ezrin and induce immunomodulatory effects. Preferred peptides are between five and thirty amino acids in length and preferred sequences are as follows. Peptides binding to Domain B of the Heprecipient: SEQ ID 3 Rupe15: TEKKR SEQ ID 4 Rupel9: TEKKRRETV SEQ ID 5 Rupe111: TEKKRRETVER SEQ ID 6 Rupe37: KKRRE SEQ ID 7 Rupe310: KKRRETVE SEQ ID 8 Rupe312: TEKKR SEQ ID 9 Rupe313: KKRRETVEREK SEQ ID 10 Rupe314: KKRRETVEREKE SEQ ID 11 Rupe411: KKRRETVER SEQ ID 12 Rupe413: KRRETVEREK SEQ ID 13 Rupe414: KRRETVEREKE SEQ ID 14 Rupe59: RRETV SEQ ID 15 Rupe614: RETVEREKE SEQ ID 16 Rupe1014: EREKE Peptide binding to Domain A and Domain B of the Heprecipient SEQ ID 18 Rupe2024: KEELM SEQ ID 19 Rupe2032: KEELMLRLQDYEE SEQ ID 20 Rupe2032p: KEELMLRLQDYpEE SEQ ID 21 Rupe2132: EELMLRLQDYEE SEQ ID 22 Rupe2132p: EELMLRLQDYpEE SEQ ID 33 Rupe2232: ELMLRLQDYEE SEQ ID 24 Rupe2232p: ELMLRLQDYpEE SEQ ID 25 Rupe2428 : MLRLQ SEQ ID 26 Rupe2832: QDYEE SEQ ID 27 Rupe2832p: QDYpEE Other peptides or other charged molecules that bind to Domain A or Domain B or the bridge of Domain A and Domain B of the Hepreceptor are pro barely biologically active These peptides or other charged molecules can be administered orally and by other routes for the treatment of various infectious diseases and cancer. How to do it The peptides used in this invention can be synthesized for example, using a solid phase method using either Boc or Fmoc chemistry or any other practical route for peptide synthesis known to those skilled in the art of peptide synthesis.

Step-form solid phase synthesis with Boc amino acids can be performed based on the Merrifield method; (Journal of American Chemical Society 85 2149-2154). The following compounds can be used (Novabiochem Resin: Boc-Glu (Obzl) -PAM, Amino Acids: Boc-Lys (2C1-Z-) 0H, Boc-Glu (Obzl) OH, Boc-Arg (Tos) OH, Boc -Val-Oh, Boc-Thr (Bzl) -OH, Solvents: DMF (Rathburn), Dichloromethane (BDH), Ethylacetate (BDH), Reagents: HBTU (Phase Separations Ltd), p-Cresol (lanchester) TFA (Halocarbon Products Corporation) HF (BOC) DIEA (Fluka) Reagent side chain protective groups recommended for Boc amino acids are :, Arg (Tos), Asn (Xan), Asp (OcHxl), Glu (Ochx) Gln (Xan) or Gln, His (DNP), Lys (CIZ), Serine (Bzl) Tyr (BrZ) Trp (CHO). The abbreviations have the following meanings: DCC = dicyclohexylcarbodiimide, DIC = Diisopropylcarbodiimide, DCM = dichloromethane, DMF = dimethylformamide, TFA = trifluoroacetic acid, Boc = t-Butyloxycarbonyl, HOBT = Hydroxybenzotriazole, DIEA = Diisopropylethylamine, DCU == Dicyclohexylurea. For example, the boc synthesis of a peptide of this invention can be carried out as follows: activation / neutralization in situ of HBTU in 0.5-mmol scale uses 0.5 mmol of resin and a three-fold excess of the activated amino acid Boc. The amino acid Boc and the activation reagent (HBTU) must be used in equimolar amounts, ie 2 mmoles each in this case equal to 3 times of excess. DIEA is used to both neutralize the resin to copy and activate the amino acid Boc (therefore 2.5 mmol, one amino acid equivalent Boc and one resin equivalent are used). Reagents: HBTU 0.5 M in DMF (MW = 379, 0.5 M = 18.95 g in 100 ml, note is not stable to light) requires 2 mmoles = 4 mi and 2.5 mmol of DIEA = 0.46 mi (MW = 129, d = 0.742). Activation of amino acids: the amino acid Boc must be activated only immediately before addition to the resin, especially in the case of Arg (Cough). For all Boc amino acids: weigh 2 mmoles of Boc amino acid in a 20 ml glass sample bottle. Add 4 ml of 0.5 M HBTU solution and stir to dissolve the solid. Add 0.46 ml of DIEA and mix (some color change can be observed). Method: wash the resin with DMF, remove the protective group of Boc with 100% TFA - Shake twice for 1 minute drain between, drain, wash the flow with DMF for 1 minute, drain, add the activated amino acid solution, stir by 10 minutes, then take the sample and perform the ninhydrin test to determine coupling efficiency. At the completion of the synthesis, wash the fjub with DMF, then DCM and dry. The synthesis of the first and each subsequent level of peptide construction is achieved using a three-fold excess of BOC amino acids activated with HBTU in DMF. In all couplings, coupling efficiency must be more than 99% as indicated by quantitative ninhydrin test. The deprotection of the N terminals in 100% TFA is performed. The resin peptide is carefully washed before and after deprotection. After the last coupling and removal of the Boc protection, the peptide resin is washed with dichloromethane and air dried. The peptide is removed from the resin support by the high HF method (2 g resin peptide, 2 g cresol, 20 ml HF, 1.5 hours at -5 ° C) to produce the unpurified peptide which is precipitated with ethyl acetate (100 ml) and redissolved in guanidine 6 M HCL - M 0.1 M Tris solution (20 ml). The peptide can be purified as follows using analytical HPLC separation on a Vydad C18 5 RAC column. HPLC grade acetonitrile (aldrich) and water are filtered through a membrane filter and degassed with helium flow before use. The analytical separation achieved with a solvent gradient starting with 0% acetonitrile, constantly increasing to 60% acetonitrile in 20 minutes, being in this concentration for twenty minutes and decreasing regularly to 0% acetonitrile for 10 minutes in a constant flow 1.2 mi per minute. Preparative separation of peptide achieved on a preparative C? 8 column TSK-GEL. The separation is achieved with a solvent gradient starting with 0% acetonitrile, constantly increasing to 18% acetonitrile in 50 minutes, then 60% acetonitrile for 80 minutes, being at this concentration for 30 minutes in a constant flow of 8 hours. my per minute The gradient can be controlled by two microprocessors controlled by single-piston pumps ilson 302. The compounds can be detected with a Waters 486 tuned Absorbance Detector at 214 nm and analytical chromatographies registered with a Laser et 5L HP. A 220 nm UV-Vis holocromo detector for preparative chromatographies can be registered with a single-channel recorder LKB 2210. The quality of capillary electrophoresis can be controlled using Waters Quanta 4000 using a phosphate buffer (75 microM) pH 2.5 run at 15 kV, sample time 20 seconds, loaded by hydostatic injection in a 60 cm column, run time 12 minutes. The yield for 1 g 0.46 mmoles of resin synthesis should be approximately 250 mg of pure peptide. Alternative solution synthesis methods can also be used to produce large amounts of the peptides of this invention. Protected trimer fragments can be obtained using stepwise synthesis by the active ester method known to those skilled in the art of peptide synthesis. The fragments are then assembled using DCC / HOBT after removal of the relevant C and N terminal protective groups. After removal of all protecting groups the unpurified peptide is partially purified in SP-Sephadex-C25 ion exchange chromatography followed by preparative HPLC then lyophilized. How to use it 0.01 to 1000 mg of lyophilized peptide can be dissolved in 1-10 ml of distilled water and administered orally or vaginally. 0.01 to 1000 mg may be formulated in a pill or capsule or suppository with carriers commonly used by those skilled in the pill or capsule manufacturing art and administered orally, or vaginally or anally. A filter-sterilized solution between 0.001 and 100 milligrams in distilled water can be injected subcutaneously or intravenously or intramuscularly. The following examples serve to illustrate the invention only, and should not be construed as limiting in any way. EXAMPLE I Adjuvant activity of Hepreceptor peptides that increase the IgQ serum antibody response to Ovalbumin in mice The IgG response in mice is determined two weeks after an injection of 50 micrograms of Ovalbumin plus various concentrations of different Heprecipient peptides. The IgG response is measured by Optical Density (OD) of a 1 to 100 dilution of mouse sera in the presence of ovalbumin. Results Response of IgG registered as DO IgG response recorded as DO after it is based on data in relation to 100 for each control Conclusion All Hepreceptor peptides with the exception of HEPl show adjuvant activity but with different optimal concentrations. EXAMPLE IB Activity of Hepreceptor peptides that increase the antibody-dependent cytotoxic response in Timo to red sheep cells (BCC) in mice. The influence of Hepreceptor peptides on the activation of antibody-forming cells against sheep erythrocytes (BCC) in mice is determined (Hybrid CBA-C57B1 Fi, 2 months old, weight 18-22 grams).

The mice are first injected intraperitoneally using either 0.5 ml of sterile saline as a control or Hepreceptor peptides in the same volume of saline. 30 minutes after the injection of Hepreceptor peptides, a cell suspension containing 5 million CCB is administered intraperitoneally to each mouse. Four days after the immunization, the mice are killed by cervical dislocation and spleens are obtained aseptically. Each spleen is homogenized in 2 ml of Medium 199, then 100 microliters of this suspension are obtained in 1 ml of agarose prepared in Medium 199 (stored in a water bath at 48 ° C), suspension of CCB is added, resulting in a concentration end of 1% agarose. 1 ml of agarose and cell mixture is stirred and then transferred to a petri dish to fix. When the agarose arrives, to be solid, incubate the Petri dish for 1 hour at 37 ° C then add 0.5 ml of guinea pig serum diluted 1 in 20 in Medium 199 on the top of the agarose gel as a source of complement. Incubation is continued for another hour. The boxes are then visualized using an 8x binocular microscope and the number of plates is counted (each plate equivalent to a mouse spleen cell that secretes antibody). The results are expressed both as a number of cells that secrete antibody per million nucleated spleen cells and the number of cells that secrete antibody per whole spleen. As no mitogenic effect is observed (administration of Hepreceptor peptide results in normal-sized mouse spleens), these two calculations give similar results. Average data (of thirty mice per data point) of the number of antibody-forming cells per one million nucleated spleen cells. The data is re-based in relation to 100 for each control group. Contr code Sequence of peptide ol peptide (Rupe312 SEQ ID 8: KKRRETVERE and Rupel5 SEQ ID 3: TEKKR and Rupel014 SEQ ID 16: EREKE and Rupel024 SEQ ID 17: EREKEQMMREKEEL and Rupe2032 SEQ ID 19: KEELMLRLQDYEE and HEPl SEQ ID 28: TEKKRRETVEREKE Conclusion All peptides of Hepreceptor increase the antibody-dependent cytotoxic response in thymus but with different optimal concentrations. EXAMPLE 2 Anti-cancer activity of Hepreceptor peptides in the growth of transplanted sarcoma of the uterus SM-322 and in cancer in the uterine cervix CUS-5 performed in CBA mice using Rupe312 and Rupe414 as examples. Materials and methods Model SM-322 of transplanted mouse sarcoma (endothelial tumor) Primary tumors of the uterus are induced in female mice using 1,2-dimethylhydrazine. A few primary tumors are transplanted into syngeneic mice. The first visible nodules begin to appear at the transplant site after 4 days. The life expectancy of the mice with transplanted tumors is 22-24 days. CUC-5 model of cervical cancer of transplanted mouse (epithelial tumor) Primary tumors are induced in female mice using methylcolantrene. They then autotransplant primary tumors in the uterine cervix. The life expectancy of mice with transplanted tumors is 43 days. CBA mice CBA female mice weigh 21.4 = / - 1.2 gram and are 2-3 months old. Tumors are introduced as 0.5 ml of tumor suspension (1 g of tumor per 10 ml of Igla medium) and ten mice are used in each treatment group. Preparation and administration of peptide The lyophilized peptide is dissolved in sterile physiological saline immediately before use in three concentrations. 0.5 ml of solution is injected twice per week into the peritoneum of the mice for the duration of the experiment. Three different concentrations of the peptide are used leading to three final doses per injection per mouse of 10, 1.0 and 0.1 micrograms.

Results The decrease in the average percentage of tumor volume was recorded in relation to the control group at the three time points. The longevity of the mice in the treatment groups and control groups is compared and the histology of the tumors is compared between the control and treatment groups. Model SM-322 of transplanted mouse sarcoma CUC-5 model of cervical cancer of transplanted mouse Peptide Concentration Decrease in volume% of Days of tumor traction in relation to control life (Rupe312 SEQ ID 8: KKRRETVERE and Rupe414 SEQ ID 13: KRRETVEREKE) Conclusion Hepeceptor peptides Rupe312 and Rupe414 reduce the proportion of growth of transplanted sarcomas of rapid growth that lead to a slight increase (3-18%) in life expectancy. The Rupe312 and Rupe414 Hepreceptor peptides reduce the growth rate of transplanted cervical cancer with minor growth but no significant increase (or decrease) in life expectancy is detected. Hepeceptor peptides Rupe312 and Rupe414 induce a non-bleeding ulcerative destruction of the tumor center in both models that consistently reach smaller tumor volumes. EXAMPLE 3 HEPl, a peptide of Hepreceptor, administered orally (10 mg per day for either thirty days or ninety days) to 21 patients infected with HIV leads to clinical improvement. The success of this study generally demonstrates the usefulness and reduction for the practice of peptides derived from the Hepreceptor. This study is carried out with pharmaceutical grade HEPl, a peptide that has a sequence identical to the part of Domain A of the Hepreceptor. Volunteers infected with HIV are recruited for study at the Institue of Immunology, Moscow under the guidance of Professor Ravshan Ataullakhanov. The HEPl pharmaceutical grade passes an extensive range of animal toxicology (rat and rabbit) and pre-clinical testing before the test begins, demonstrating the safety of the compound. (Preliminary assessment of negative toxicity, Effect of lOOOx negative therapeutic dose, Negative local irritation, influence on CNS and negative HVS, negative sub acute toxicity, mutagenic negative effects, chronic negative toxicity, negative embryotoxicity). Study plan Orally administered to patients with a 10 mg solution of HEPl in 2 ml of sterile distilled water once a day in the morning before breakfast (the solution is prepared and stored and separated into batches of 10 mg at -20 ° C). A coded placebo solution of distilled water is administered to all patients for thirty days before treatment. It is administered to a first group of 11 patients with HEPl for 90 days and a second group of 10 patients is administered HEPl for 30 days fifteen months later, after which the data of the first group of patients have been analyzed. During the treatment period, patients are requested to attend the clinical examination once a week, undergo a medical examination and give a blood sample for analysis. Patients are also asked to cooperate with post-treatment monitoring and attend the clinical examination once a month for six months for additional medical examinations and donations of blood samples. 21 of the 21 patients cooperate with the monitoring during the treatment period and 14 of the 21 patients agree with the post treatment monitoring. Patients are not recipients of any other anti-retroviral therapy during or a month before the treatment of HEPl. Patients Patients are recruited from several Moscow clinics and give informed written consent to participate in the trial. They are identified as infected with HIV by a positive ELISA, have depressed T-cell counts and experience some clinical manifestation of HIV-related disease. It is subsequently shown that patients have a range of CD4 cells per microliter between 17 and 801 and a range of HIV RNA serum (quantitative PCR assay of Roche Labs Amplicor) from non-detectable to 230,000 copies per ml. Characteristics of the patient as start of the test General observations Patients report no adverse reactions to HEPl, and 17 patients report that they generally feel better and gain between 1.5 kg and 4.5 kg in weight while on HEPl therapy (a patient also feels better during the placebo period). Adverse reactions No adverse reactions are detected. Clinical evaluations including ultrasound exams and an extensive series of blood tests biochemical, hematological, immunological and urine tests. Opportunistic infections Opportunistic infections are detected by microbiological analysis and patients treated by HEPl are either stable without new infections or they decline infections. For example, before treatment 38% of patients have severe Candida Albicans infection of farineus, after treatment only 9% are severely infected. Before treatment, 52% of patients have severe S. viridans infection of farineus, after treatment only 33% are severely infected. Before treatment, 33% of patients have S. aureus del farineo infection, after treatment only 19% are infected. CD4 T lymphocytes The group of eleven patients treated for three months with HEPl experiences an average gain in T cell number of 9% by the end of treatment and 32% on average over the following six months after treatment. The group of ten patients who are treated for one month with HEPl experience an average gain in the number of T cells of 3% by the end of treatment and 20% on average over the next six months after treatment. Continuous improvement suggests that a positive immune change has been induced in patients. HIV infectivity assay by TCID Viral load is measured by mixing HIV-infected peripheral blood mononuclear cells (PBMC) from the patient with PBMC from uninfected donor at a ratio between sample cells to 1/16 culture cells and cultivate at 37 ° C for fourteen days. The viral load of the culture is measured by the Innogenetics HIVp24 assay and the results in picograms of the HIVp24 antigen are recorded by me. Three month treatment One month treatment In both groups of patients (Pl-Pll and P12-P76), a general pattern of infectivity is observed in the f ID assay to detect infectious virus particles. At the start of HEPl therapy, (Phase 0-Phase 1), the virus burden of infectious HIV declines quite low at the first three weeks of treatment and in 9 out of 21 falls to at least zero one week. Three patients experience an increase in infectivity during the first week of treatment before the infectivity falls to zero in the second week. In the second phase that follows, (Phase 2), in most patients HIV infectivity increases between 2X and 600X between four and eight weeks after the start of treatment. Patients do not report worsening of their condition during this period. Phase 3 which follows where infectivity declines to previous pretreatment levels. In Phase 1, the average maximum decline in virus levels below the pre-treatment baseline is less than 80%. In Phase 2, the maximum increase The average number of viruses in Phase Two is 22 times. In Phase 3, the average maximum virus decline below the pre-treatment baseline is less than 64%. During Phase 3, viral infectivity declined to zero in three patients. Six months after the end of treatment with HEPl, the viral effectiveness usually returns to pre-treatment levels. These results are interpreted as showing that the immune system is activated by HEPl to fight HIV in Phase one. The increased level of activation in the immune system stimulates the activation of a deposit of cells infected in a latent form with HIV that leads to the increase in infectious virus in Phase 2. Finally in Phase 3, the activated immune system successfully destroys the deposit of newly activated virus. The group of ten patients treated for only one month with HEPl shows that the progression through Phase 2 and Phase 3 does not depend on the presence of HEPl. HIV viral load by quantitative plasma HIV RNA PCR Viral load analysis performed by the Roche Labas PCR assay: Amplicor HIV-1 Monitor In most patients of both the one-month and three-month treatment, similar phases of viral suppression are observed (Phase 1) followed by temporary viral activation (Phase 2) followed by suppression (Phase 3) that is similar to TCID data. Phase 1 lasts between one and four weeks and viral load declines on average by less than 47%. Phase 2 lasts between eight and four weeks (a more sustained period than that observed with the TCID assay) and the viral RNA in the plasma increases on average by 3X. This is followed by Phase 3 in which the viral RNA in the plasma falls below the pre-treatment levels by an average reduction of less than 19%. Cell populations and expression of cell surface markers by cytometry. Cell surface markers in peripheral blood mononuclear cells from the group of ten patients (P12-P76) treated for one month with HEPl are analyzed in detail using microscopy, fluorescently labeled antibodies, flow cytometry and related procedures. Treatment with HEPl has the following effects in each cell population averaged by the group of 10 patients: a) Lymphocytes An average increase of 7% in absolute number of lymphocytes during treatment and an increase of 25% for the five months following treatment. b) Leukocytes An average increase of 10% during treatment and an increase of approximately 20% for the five months following treatment. c) Natural killer cells An average increase of 10% during treatment and an increase of approximately 30% for the five months following treatment. d) B cells An average increase of 5% during treatment and an increase of approximately 80% for the five months following treatment. e) CD3 expression cells An average increase of 15% during treatment and an increase of approximately 30% for the five months following treatment. f) CD8 expression cells An average increase of 15% during treatment and an increase of approximately 20% for the five months following treatment. g) CD44-CD4 expression cells An average increase of 25% during treatment and an increase of approximately 260% for the five months following treatment. h) CD44-CD8 expression cells An average increase of 12% during treatment and an increase of approximately 30% for the five months following treatment. i) Level of expression of HLA Class I in CD4 cells An average increase of 10% during treatment and an increase of approximately 70% for the five months following treatment. j) Level of expression of HLA Class I in CD8 cells An average increase of 10% during treatment and an increase of approximately 70% for the five months following treatment k) Cells expressing CD25-CD8 An average increase of 5% during treatment from low levels and an increase of approximately 100% for the five months following treatment. The CD25-CD4 cells shows no significant variation. 1) Cells expressing CD38-CD4 An average increase of 2% during treatment from low levels and a decrease of approximately 15% for the five months following treatment. m) Cells expressing CD38-CD8 An average increase of 2% during treatment from low levels and a decrease of approximately 25% & for the five months following treatment. (The significant decrease in CD38 is discussed in the next section). Other markers such as CD28, HLA-DR, CD45RO, CD45RA, CD57, CD62L, do not show significant changes or 5 consistent patterns between patients. CD38-CD8 cells: prognostic indicator for progression to AIDS It is well recognized that the increased decrease in the population of CD38-CD8 expressing cells correlates with the development of SIDa in patients infected with HIV. M. Levancher, F Hulstaert, S. Tallet, S Ullery, J J Pocidalo, B A Bach (1992) "The significance of activation markers on CD8 lymphocytes in human immunodeficiency syndrome: staging and prognostic valué "Clinical Experimental Immunology 90 376-382 Briefly, CD38-CD8 cells as a percentage of the total CD8 population correlate with a progression of HIV disease, an observation that has been verified in a more recent publication number. In healthy people, the percentage of CD8 cells that also express CD38 is between 30-50%, in HIV-infected patients asymptomatic it is between 50-65%, in patients infected with HIV with ARC it is between 65% and 80% and in patients with AIDS 25 between 80 and 98%. In the follow-up of the study of ten ^^? llj &gj patients who take 10 mg of HEPl orally for a month, 5 patients provide blood samples for analysis. In all these patients it is clear that the population of CD38-CD8 cells as a percentage of the total CD8 population declines towards values indicating lower risk of HIV disease and improvement in health.

Antibodies against HIV in plasma At the end of the one month treatment with HEPl of 10 patients (P12-P76), 5 patients show antibody titers. significantly higher against several HIV antigens (titers based on 100 before treatment).

Antibody responses to opportunistic infections Treatment with HEPl stimulates antibody responses to opportunistic infections (antibody titration based on 100 before treatment) The average increase in antibody titration is more than 23% for Aspergillus IgG, more than 78% for Candida IgG, more than 50% for CMV IgG, more than 38% for CMV IgM, more than 15% for IgM of HSV1, more than 51% for HSV2 IgM and more than 5% for toxoplasma IgG. Conclusion The above data are consistent with the invention that a peptide with a sequence identical to the Hepreceptor part reaches immune activation and clinical benefits in human clinical testing of patients with HIV.

EXAMPLE 4 Severe acute and chronic Candida infection in women can be cured by the immune response resulting from Hepreceptor stimulation Clinical study: recurrent moderate candida infection A woman (age 27) with recent untreated outbreak of Candida infection is voluntary for the study. She reports recurrent moderate vaginal Candida infection (six episodes in the previous twelve months) that has been previously treated with intra vaginal vaginal clotrimazole 1%. She self-administered 5 ml of a lmg / ml solution of HEPl intravaginally with a 5 ml syringe on two consecutive days. After three days all the clinical symptoms of Candida infection have disappeared and she reports not having additional recurrences of Candida infection in the following 12 months. Three female patients who are treated at the Nearmedic Plus STD clinic in Moscow are volunteers for the study who have suffered from severe Candida infection of the vagina after they have been treated with antibiotics for several genitourinary infections. Patients are treated with 5 ml of a 2 mg / ml solution of HEPl for three consecutive days (no other antifungal treatment is used). The comparison of microbiological analysis (culture of urethral scrapes, cervical and vaginal canal) and clinical analysis before treatment and three weeks after treatment show either significant improvement or elimination of the infection.

EXAMPLE 5 Rupe312, Rupe414, Rupelll and Rupe411 induce strong macrophage activation response in mice. A number of peptides derived from Domain A of the Heprecipient including HEPl are studied in mice Induction of activated macrophages Groups of three mice (CDAxC57Bl) weighing 22-24 g are injected. Abdominally with each peptide solution of 1.0 micrograms of peptide dissolved in 0.5 ml of physiological saline. After 24 hours they kill the animals using dislocation of the neck vertebrae and inject 5 ml of Hanks' solution into the abdomen. The abdomen is massaged for 30 seconds and then the peritoneal fluid is collected. Is the collected liquid filtered using a nylo filter? in siliconized tubes containing 1.5 mg / ml EDTA. The number of cells containing nucleus is then evaluated in 1 microgram of filtrate under microscopic examination using a Nihon hemocytometer. The cells are granulated by centrifugation for 5 minutes in 800 g., the pellet is resuspended in fetal calf serum, the cell suspension is dripped onto a slide and dried then fixed in methanol and stained with Romanovski staining agent. The morphological analysis of the cells of the peritoneal exudate is performed using an Opton optical microscope in amplifications of 1600. The number of lymphocytes, macrophages at rest, activated macrophages, granulomatous and other cell types is evaluated. The result is that the peptides all increase the number of activated macrophages but Rupelll, Rupe312, Rupe411 and Rupe414 are significantly more active than HEPl.

HEPl SEQ ID 28: TEKKRRETVEREKE Rupelll SEQ ID 5: TEKKRRETVER Rupe312 SEQ ID 8: KKRRETVERE Rupe411 SEQ ID 11: KRRETVER Rupe414 SEQ ID 13: KRRETVEREKE EXAMPLE 6 In vitro activation of human peripheral blood mononuclear cells by Hepreceptor peptides demonstrated by measuring the incorporation of radioactive labeled thymidine into the DNA of growing cells Peripheral blood mononuclear cells (PMBC) are separated from the peripheral blood of a healthy donor using the standard method of fractionation in a ficoll gradient. PBMCs are suspended in culture medium containing RPMI1640 medium plus 10% fetal calf serum, 1 mM L-glutamine and antibiotics (BM). The cell suspension is placed in wells of 96 microwell plate holes for cell culture (100 microliters of suspension containing 100,000 cells per well). Then add 100 microlitors of BM containing peptide (final concentration 0.001-10 microgram / m). The negative control well contains BM but no peptide. The plate is incubated at 37 ° C for three days then 3H radioactive thymidine is added to a final concentration of 1 microcurie per ml. The incorporation of 3H thymidine into the DNA of the cells is measured using a beta counter using standard procedures. The experiment is repeated twice and the results are expressed as an average of the two experiments, in radioactive counts per minute. The result shows that all peptides activate mononuclear cell proliferation but that Rupe312 and Rupe414 are significantly more active than HEPl with peak activity around 3 nanograms / ml.

HEPl SEQ ID 28: TEKKRRETVEREKE Rupel9 SEQ ID 4: TEKKRRETV Rupe312 SEQ ID 8: KKRRETVERE Rupe414 SEQ ID 13: KRRETVEREKE Rupe411 SEQ ID 11: KRRETVER Rupelll SEQ ID 5: TEKKRRETVER Rupe614 SEQ ID 18: RETVEREKE EXAMPLE 7 Effect of Hepreceptor peptides on MHC Class I expression in several immunological cells Incubation of peptides derived from Hepreceptor (0.003 micrograms per ml) with human white cells (CB) for 24 hours at 37 ° C, results in a fall in the intensity of HLA expression in the cellular surface of all CCB (due to cellular activation and internationalization of the receiver). Rupe312 is more active than Rupe414, which is more active than HEPl. Data based on 100 for the control value in the absence of peptides A cell specific effect of this activation is an increase in the population of monocytes expressing MHC Class I and a decrease in CD8 lymphocyte population expressing MHC Class I. Data based on 100 for the control value in the absence of peptides (Rupe312 SEQ ID 8: KKRRETVERE and Rupe414 SEQ ID 13: KRRETVEREKE) EXAMPLE 8 Hepreceptor peptides suppresses production of IL-8 in CCB The suppressive effect of increased concentrations of Rupe312, a peptide Hepreceptor, on the expression of IL-8 is detected by human BCC after 48 hours of incubation at 37 ° C. EL-8 is a chemotactic factor that occurs in response to an inflammatory stimulus that attracts and activates T cells, neutrophils, basophils, granulocytes but not monocytes / macrophages. Inhibition of IL-8 plays a role in the selective activity of Rupe312 in activating monocyte macrophages. The measurement of IL-8 provides an assay to determine the activity of several peptides derived from Hepreceptor.

(Enasyo of IL-8 EIA manufactured by Innogenetics, Belgium) (Rupe312 SEQ ID 8: KKRRETVERE) EXAMPLE 9 Very low dose of Hepreceptor peptides (1-100 nanograms / mouse) protects mice from acute infection with Salmonella tryphimurium. Laboratory mice are divided (hybrids from CBAxC57Bl Fl) in groups of five that either receive 0.5 ml of saline or 0.5 ml of saline plus several concentrations of different Hepreceptor peptides (1, 10 or 100 nanograms). 24 hours later the mice are infected with Salmonella typhimurium (10,000 or 100,000 bacteria injected intraperitoneally per mouse). The percentage of each group of mice that survive after 20 days is recorded (control animals infected lethally die within three days of infection). Percentage of mouse group that survives after 20 days of infection (Rupel5 SEQ ID 3: TEKKR and Rupel024 SEQ ID 17: EREKEQMMREKEEL and HEPl SEQ ID 28: TEKKRRETVEREKE) Conclusion Hepreceptor peptides protect animals from lethal bacterial infection.

EXAMPLE 10 Very low dose of Hepreceptor peptides (1-1000 nanograms / mouse) improves the survival time in mouse lethal herpes virus infection model. White B / P laboratory mice are injected (five per group) intraperitoneally with peptide from Hepreceptor (1-100 nanograms per mouse) 48 hours and 24 hours before a lethal injection of the herpes virus (VPG-1 strain L2) in a titre of 3.5 LD50 in 0.2 ml of medium. The average survival time in days per group of mice is recorded (hepl seq id 28: TEKKRRETVEREKE) Conclusion The Hepreceptor peptides significantly increase the survival time of lethal viral infection. Priority documents UK patent application GB9921881L .0, Holms r., September 17, 1999.

Patent Documents United States Patent 5,773,573 Rupert Holms June 30, 1998. Other publications Ossi Turunen, Markku Sainio, Juha Jaaskelainen, Olli Carpen, Antti Vaheri (1998) "Structure- Function in the ezrin family and the effect of tuphor-associated point mutations in neurofibromatosis 2 protein" Biochi ica et Biophysica Acta 1387: 1-16 Anthony Bretscher, David Reczek and Mark Berryman (1997) "Ezrin: a protein requiring conformational activation to link microfilaments to the plasma membrane in the assembly of cell surface structures" Journal of Cell Science 110: 3011-3018 Claudia Hecker, Christoph Weise, Jurgen Schneider-Schaulies, Harvey Homes, Volker ter Meulen (1997) "Specific binding of Hiv-1 envelope protein gpl20 to the structural membrane proteins ezrin and moesin" Virus Research 49: 215-223 M Levancher, F Hulstaert, s. Tallet, S Ullery, J J Pocidalo, B A Bach (1992) "The significance of activation marker on CD8 lymphocytes in human immunodeficiency syndrome: staging and prognostic valué" Clinical Experimental Immunology 90 376-382 Stephan Oehen and Karin Brduscha-Riem (1998) "Differentiation of Na? Ve CTL to Effector and Memory CTL: Corrleation of Effector Function with Phenotype and Cell Division "The Journal of Immunology 161 5338-5346 SEQUENCE LIST GENERAL INFORMATION NUMBER OF SEQUENCES: 2S INFORMATION FOR SEQ ID 1 SEQUENCE CHARACTERISTICS: LENGTH: 32 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear MOLECULAR TYPE: peptide SEQUENCE DESCRIPTION INFORMATION FOR SEQ ID 2 SEQUENCE CHARACTERISTICS: LENGTH: 34 amino acids XY E: amino acid STRANDEDNESS: single TOPOLOGY: linear MOLECULAR TYPE: peptide SEQUENCE DESCRIPTION SEQ ID 2 Heprecipitor Domain B MREKEELMLRLQDY (P) EEKTKKAERELSEQIQRALQ 1 5 10 15 20 25 30 INFORMATION FOR SEQ ID 3 SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear MOLECULAR TYPE: peptide SEQUENCE DESCRIPTION SEQ ID 3 Rupel5: TEKKR 1 5 1/8 INFORMATION FOR SEQ ID 4 SEQUENCE CHARACTERISTICS LENGTH 9 amino acids TYPE amino acid STRANDEDNESS single TOPOLOGY AND linear MOLECULAR TYPE peptide SEQUENCE DESCR1PTION SEQ ID 4 Rupe 19 TEKKRRETV 1 5 INFORMATION FOR SEQ ID 5 SEQUENCE CHARACTERJSTICS LENGTH 1 1 amipo acids TYPE amuio acid STRANDEDNESS stngle TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRJPTION SEQ ID 5 Rupel l l TEKKRRETVER 1 5 10 INFORMATION FOR SEQ ID 6 SEQUENCE CHARACTER1STICS LENGTH 5 apuno TYPE animo acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 6 Rupe37 KKRRE 1 5 INFORMATION FOR SEQ ID 7 SEQUENCE ChARACTERISTICS LENGTH 8 amino acids TYPE ammo acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 7 Rupe310 KKRRETVE 1 5 2/8 INFORMATION FOR SEQ ID 3 SEQUENCE CHARACTERISTICS LENGTH lO amino acids TYPE amtno aciu STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID S Rupe312: KKRRETVERE 1 5 10 INFORMATION FOR SEQ ID 9 SEQUENCE CHARACTERJSTICS LENGTH: amino acids TYPE amino acid STRANDEDNESS. single TOPOLOGY- linear MOLECULAR TYPE peptide SEQUENCE DESCR1PTION SEQ ID 9 Rupe313: KKRRETVEREK 1 5 10 INFORMATION FOR SEQ ID 10 SEQUENCE CHARACTERISTICS LENGTH- 12 am? No aads TYPE- amino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 10 Rupe314: KKRRETVEREKE 1 5 10 INFORMATION FOR SEQ ID 11 SEQUENCE CHARACTERISTICS LENGTH 8 amino acids TYPE ammo acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRJPTION SEQ ID 1 1 Rupe411: KRRETVER 1 5 3/8 INFORMATION FOR SEQ ID 12 SEQUENCE CHARACTERISTICS LENGTH 10 amino acids TYPE omino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 12 Rupe413 KRRETVEREK 1 5 10 INFORMATION FOR SEQ ID 13 SEQUENCE CHARACTERISTICS LENGTH 11 amino acids TYPE ammo acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 13 Rupe414 KRRETVEREKE 1 5 10 INFORMATION FOR SEQ ED 1 SEQUENCE CHARA CTERIST1CS LENGTH 5 amino acids TYPE amino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 14 Rupe59 RRETV INFORMATION FOR SEQ ID 15 SEQUENCE CHARACTERISTICS LENGTH 9 amino acids TYPE amino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 15 Rupe614 RETVEREKE 1 5 4/8 INFORMATION FOR SEQ ID 16 SEQUENCE CH ARACTERISTICS LENGTH 5 amino acids TYPE amino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRJPTION SEQ ID 16 RupelOH EREKE 1 5 INFORMATION FOR SEQ ID 17 SEQUENCE CHARACTERISTICS LENGTH 14 amino acids TYPE amino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 17 Rupe 1024 EREKEQMMREKEEL 1 5 10 INFORMATION FOR SEQ ID 18 SEQUENCE CHARA CTERISTICS LENGTH 5 amino acids TYPE amino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRJPTION SEQ ID 18 Rupe2024 KEELM 1 5 INFORMATION FOR SEQ ID 19 SEQUENCE CHARACTERISTICS LENGTH 13 ainiiio acids TYPE amino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 19 Rupe2032 KEELMLRLQDYEE 1 5 10 /8 INFORMATION FOR SEQ ID 20 SEQUENCE CHARACTERISTICS LENGTH 13 amino acids TYPE amino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRJPTION SEQ ID 20 Rupe2032p KEELMLRLQDYpEE 1 5 10 INFORMATION FOR SEQ ID 21 SEQUENCE CHARACTERISTICS LENGTH 12 ammo acids TYPE amino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRJPTION SEQ ID 21 Rupe2132 EELMLRLQDYEE 1 5 10 INFORMATION FOR SEQ ID 22 SEQUENCE CHARA CTERISTICS LENGTH 12 ammo acids TYPE a ino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 22 Rupe2132p EELMLRLQDYpEE 1 5 10 INFORMATION FOR SEQ ID 23 SEQÚENSE CHARACTERISTICS LENGTH 1 1 amino acids TYPE amino acid STRANDEDNESS single TOPOLOGY linear MOLECULAR TYPE peptide SEQUENCE DESCRIPTION SEQ ID 23 Rupe2232 ELMLRLQDYEE 1 5 10 6/8 INFORMATION FOR SEQ ID 24 SEQUENCE CHARACTERJSTICS LENGTH. 1 1 amino acids TYPE. amino acid STRANDEDNESS. TOPOLOGY single. linear MOLECULAR TYPE peptide SEQUENCE DESCRJPTION SEQ ID 24 Rupe2232p: ELMLRLQDYpEE 1 5 10 INFORMATION FOR SEQ ID 25 SEQUENCE CHARACTERISTICS LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY- linear MOLECULAR TYPE: peptide SEQUENCE DESCRIPTION SEQ ID 25 Rupe2428: MLRLQ 1 5 INFORMATION FOR SEQ ID 26 SEQUENCE CHARACTERJSTICS: LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS single TOPOLOGY: linear MOLECULAR TYPE peptide SEQUENCE DESCRJPTION SEQ ID 26 Rupe2832: QDYEE 1 5 INFORMATION FOR SEQ ID 27 SEQUENCE CHARACTERISTICS- LENGTH. 5 ammo acids TYPE: amino acid STRANDEDNESS. TOPOLOGY single. linear MOLECULAR TYPE. peptide SEQUENCE DESCRIPTION SEQ ID 27 Rupe2832p: QDYpEE 7/8 INFORMATION FOR SEQ ID 28 SEQUENCE CHARACTERISTICS: LENGTH: 14 amino acids TYPE: amino acid STRANDEDNESS- single TOPOLOGY: linear MOLECULAR TYPE: peptide SEQUENCE DESCRJPTION SEQ ID 28 HEP l: TEKKRRETVEREKE 1 5 10 8/8

Claims (30)

1. 57
2. CLAIMS 1. A charged molecule characterized by binding to the Heprecipient. 2. A peptide characterized by a sequence identical to the Heprecipient part.
3. 3. A peptide according to claim 1, between five and thirteen amino acids in length characterized in that it has a sequence identical to the part of the Heprecipient.
4. 4. A peptide characterized in that it comprises the amino acid sequence: AREEKHQKQLERQQLETEKKR RETVEREKEQM
5. 5. A peptide characterized in that it comprises the amino acid sequence: MREKEELMLRLQDY (p) EEKTKKAERELSEQIQRALQ
6. 6. A peptide characterized in that it comprises the amino acid sequence: TEKKR
7. 7. A peptide characterized in that comprises the amino acid sequence: TEKKRRETV
8. 8. A peptide characterized in that it comprises the amino acid sequence: TEKKRRETVER
9. 9. A peptide characterized in that it comprises the amino acid sequence: KKRRE
10. 10. A peptide characterized in that it comprises the amino acid sequence: KKRRETVE
11. 11. A peptide characterized in that it comprises the amino acid sequence: KKRRETVERE
12. 12. A peptide characterized in that it comprises the sequence of amino acids: KKRRETVEREK
13. 13. A peptide characterized in that it comprises the amino acid sequence: KKRRETVEREKE
14. 14. A peptide characterized in that it comprises the amino acid sequence: KRRETVER
15. 15. A peptide characterized in that it comprises the amino acid sequence: KRRETVEREK
16. 16. A peptide characterized in that it comprises the amino acid sequence: KRRETVEREKE 59
17. 17. A peptide characterized in that it comprises the amino acid sequence: RRETV
18. 18. A peptide characterized in that it comprises the amino acid sequence: RETVEREKE
19. 19. A peptide characterized in that it comprises the amino acid sequence: EREKE
20. 20. A peptide characterized in that it comprises the amino acid sequence: EREKEQMMREKEEL
21. 21. A peptide characterized in that it comprises the amino acid sequence: KEELM
22. 22. A peptide characterized in that it comprises the amino acid sequence: KEELMLRLQDYEE
23. 23. A peptide characterized in that it comprises the amino acid sequence: KEELMLRLQDYpEE
24. 24. A peptide characterized in that it comprises the amino acid sequence : EELMLRLQDYEE 60
25. 25. A peptide characterized in that it comprises the amino acid sequence: EELMLRLQDYpEE
26. 26. A peptide characterized in that it comprises the amino acid sequence: ELMLRLQDYEE
27. 27. A peptide characterized in that it comprises the amino acid sequence: ELMLRLQDYpEE
28. 28. A peptide characterized in that it comprises the amino acid sequence: MLRLQ
29. 29. A peptide characterized in that it comprises the amino acid sequence: QDYEE
30. 30. A peptide characterized in that it comprises the amino acid sequence: QDYpEE 61 SUMMARY OF THE INVENTION This invention describes novel charged molecules that specifically bind to Hepreceptor, a regulatory site that has been discovered in human ezrin. This invention is that when peptides or other charged molecules bind to the Heprecipient, medically useful immune responses are induced. These charged molecules can be administered orally and by other routes for the treatment of various infectious diseases and cancer. It has been determined that the Hepreceptor (human ezrin 308-373) comprises two adjacent helical alpha domains that are bent together in a hinge region (M339-M340) and is stabilized by side chain charges complementary to the primary amino acid sequence in the soluble cytoplasmic conformation of ezrin. It has been determined that the unfolded membrane is associated with the conformation of ezrin, the Hepreceptor is pulled through the cell membrane and exposed on the outer surface of the cell. Domain A of the Heprecipient (amino acids number 308-339 of human ezrin) comprises the following sequence of 32 amino acids. SEQ ID 1 A R E E K H Q K Q L E R Q Q E K K R R E T V E R E K E Q M Heprecipher domain b (amino acids numbers 340-373 of human ezrin), comprises the following sequence of 34 amino acids (Tyrosine 353 [Y] can be phosphorylated to phosphotyrosine [Yp] in the membrane associated with conformation 62 of ezrin): SEQ ID 2 M R E K E E L M L R L Q D Y (p) E E K T K K A E R E L S E Q I Q R A L Q.