CN1437442A - Peptide analogs and mimetics suitable for in vivo use in the treatment of diseases associated with abnormal protein folding into amyloid, amyloid-like deposits or beta-sheet rich pathological - Google Patents
Peptide analogs and mimetics suitable for in vivo use in the treatment of diseases associated with abnormal protein folding into amyloid, amyloid-like deposits or beta-sheet rich pathological Download PDFInfo
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- CN1437442A CN1437442A CN00819247A CN00819247A CN1437442A CN 1437442 A CN1437442 A CN 1437442A CN 00819247 A CN00819247 A CN 00819247A CN 00819247 A CN00819247 A CN 00819247A CN 1437442 A CN1437442 A CN 1437442A
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Abstract
The present invention is an inhibitory peptide capable of inhibiting beta pleated sheet formation in amyloid beta -peptide. The inhibitory peptide is a beta sheet breaker peptide analog designed by chemical modification of beta sheet breaker peptide capable of inhibiting beta pleated sheet formation in amyloid beta -peptide. The present invention also includes an inhibitory peptide capable of inhibiting conformational changes in prion PrP protein associated with amyloidosis. The inhibitory peptide being a beta sheet breaker peptide analog designed by chemical modification of a beta sheet breaker peptide capable of inhibiting the conformational changes in prior PrP protein associated with amyloidosis. In addition, the present invention includes a peptide mimetic with the structure PMiA beta 5. In another embodiment, the peptide mimetic has the structure PMiPrP13. In yet another embodiment, the peptide mimetic has the structure PMiPrP5.
Description
The application requires the priority of No. the 60/163rd, 911, the U.S. Provisional Application of on November 5th, 1999 application.
Background of invention
Invention field
The present invention relates to peptide analogues and peptide mimics that beta sheet destroys peptide, described peptide analogues and peptide mimics are suitable for using in the body treatment mammalian proteins matter conformation disease, for example Alzheimer's and prion disease.More particularly, the present invention relates to new type of peptides analog and peptide mimics, comprise the Pharmaceutical composition of a kind of in described peptide analogues and the peptide mimics or their mixture, and relate to and be used to prevent, treat or detect obstacle or the disease relevant: be folded into amyloid or the sedimental paraprotein of amyloid sample or it has the precursor of pathogenic beta sheet structure with following composition.
Description of related art
Having accumulated mass data shows: several different obstacles have identical molecular basis, and promptly protein conformation changes (Thomas etc., Trends Biochem.Sci.
20: 456-459,1995; Soto, J.Mol.Med.77:412-418,1999).These protein conformation diseases comprise Alzheimer's, prion correlation obstacle, SA, serpin defective obstacle, Huntington disease and amyotrophic lateral sclerosis (Soto 1999, see above).The sign of protein conformation obstacle is that the primary structure of normal protein does not change, but secondary structure and tertiary structure change.Conformational change albumen may cause disease (Thomas etc., 1995, see above) by direct toxicity activity, the biological function that lacks normal folded protein or inappropriate transportation.Under the virose situation of described albumen, described albumen usually in Different Organs self-association and the deposition become amyloid fibrils, cause tissue damage (Thomas etc., 1995, see above; Kelly, Curr.Opin.Struct.Biol.
6: 11-17,1996; Soto, 1999, see above).
Alzheimer's (AD) is destructive neurodegenerative disease, it is characterized in that losing short-term memory, disorientation and judgment and inferential capability and weakens.AD is a most common dementia in the elderly population.According to estimates, there is influence (Teplow, the Amyloid that is subjected to AD above 2,005 million peoples to some extent in the whole world
5: 121-142,1998).The sign of AD is that soluble protein aggregation body (being called amyloid) is deposited in brain essence and the cerebral blood vessel wall.The main component of amyloid is the 4.3KDa hydrophobic peptide that is called amyloid beta peptide (A β), described peptide as the part of a kind of longer precursor protein (APP) by chromosome 21 coding (Selkoe, Science
275: 630-631,1997).Genetics, biochemistry and the neuropathology evidence strong hint of the accumulation of past 10 years: amyloid plays an important role in the early stage pathogenesis of AD, and may trigger this disease (Soto etc., J.Neurochem.
63: 1191-1198,1994; Selkoe, 1997, see above; Teplow, 1998, see above; Sisodia and Price, FASEB J.
9: 366-370,1995; Soto, Mol.Med.Today 5:343-350,1999).
Amyloid is a generic term, describes fibrillation aggregation (Serpell etc., Cell Mol.Life Sci. with common structure motif (being the beta sheet conformation)
53: 887,1997; Sipe, Ann.Rev.Biochem.
61: 947-975,1992).Described aggregation shows the specific stain characteristic, comprises with the ability of sending green birefringent light behind the congo red staining, and the ability of binding fluorescent dyes thioflavine S (Sipe, 1992, see above; Ghiso etc., Mol.Neurobiol.
8: 49-64,1994).Have to surpass 12 kinds of etiologic etiological human diseasess of difference and be characterised in that amyloid extracellular deposition in different tissues, cause cellular damage, organ dysfunction is unusual and dead.Relate in the disease of amyloidosis at these, outstanding is Alzheimer's, prion correlation obstacle (being also referred to as TSE) and SA (table 1).Amyloid fibrils is made up of proteolytic fragments normal or the mutator gene product usually.Have and surpass 16 kinds of different albumen (table 1) that relate to amyloid deposition in different tissues (Ghiso etc., 1994, see above).
The basic problem that amyloid forms is a protein folding, the wherein main soluble peptide that curls at random take the beta sheet conformation flock together (Kelly, 1996, see above; Soto, 1999, see above).The formation of amyloid is such: between the amyloid generation intermediate of conformational change hydrophobic interaction takes place, described intermediate structurally forms the beta sheet conformation when peptide interaction.Hydrophobicity it seems that for inducing the monomer that causes gathering to interact be important, and the beta sheet conformation may determine the gathering order in the amyloid fibrils.In the effort that suppresses amyloid fibrils formation, come separately this two specific character by the design short synthetic peptide, described short synthetic peptide has and the sequence homology in the peptide territory that relates to conformational change and the hydrophobicity of similarity degree, but the tendency of taking the beta sheet conformation very low (be called beta sheet and destroy peptide) (Soto etc., 1996, see above; Soto etc., 1998, see above).Target is the peptide that design has following ability: specificity generates peptide in conjunction with amyloidosis, generates the compound (Soto, 1999, see above) of the stability stablize physiology conformation, the unusual conformation of the described peptide of destruction.
Table 1. relates to the obstacle of amyloidosis and the protein ingredient of amyloid fibrils
| Disease | The fibrillation composition |
| Alzheimer's Primary Systemic Amyloidosis Secondary cases SA; The senile SA of familial Mediterranean fever SE; Familial amyloid polyneuropathy hemodialysis-associated amyloidosis heredity cerebral amyloid angiopathy; Iceland's type familial amyloidosis, the sex change of the non-neuropathic SA of Finland's type type ii diabetes familial amyloid polyneuropathy medullary carcinoma of thyroid gland atrium amyloidosis heredity heredity amyloidosis of kidney islet amyloid sample | Fragment atrial natriuretic peptide lysozyme or its fragment fibrinogen fraction insulin of the fragment calcitonin of the fragment apolipoprotein A-1 of the fragment transthyretin of the fragment prion protein of amyloid beta protein light chain immunoglobulin or its fragment serum amyloid A protein and fragment B2M Cystain C gelsolin fragment islet amyloid sample peptide thereof |
| Amyloidosis of aging | Apolipoprotein A-1 I |
At present, design beta sheet and destroyed peptide relates separately to Alzheimer's and prion disease with blocking-up pathogenetic a and the middle conformational change that occurs of prion protein (PrP).Formerly technology shows: destroy the peptide conformation change that peptide (being called iA β 1 and iA β 5) suppresses to cause amyloid formation with 11 residues and the 5 residue beta sheets of A β center hydrophobic region homology, and at the preformed fibrillation of dissolution in vitro (Soto etc., Biochem.Biiophys.Res.Commun.
226: 672-680,1996; Soto etc., Nature Med.
4: 822-826,1998).In addition, in cell culture experiments, described 5 residue peptide can be prevented owing to forming the neuronal death that the oligomerization A beta structure be rich in beta sheet causes (Soto etc., 1998, see above).In addition, by using intracerebral injection A β 1-42 to induce the amyloidosis rat model, formerly technology shows: inject described 5 residue beta sheets altogether and destroy peptide minimizing brain A β deposition, and block the deposition (Soto etc. of rat brain Central Plains cellulose starche sample pathology fully, 1998, see above).At last, inject described beta sheet destruction peptide after eight days at injection A β and can decompose preformed A β fibrillation in the rat brain in vivo, cause the size of amyloid deposition to reduce (Sigurdsson, Frangione, Soto, the manuscript of submission).What is interesting is, destroy peptide by beta sheet and remove the relevant brain tissue damage of amyloid protein recovery, comprise that neuron shrinkage and microglia cell activate.
Also design beta sheet and destroyed the conformational change that peptide is caused by prion (PrP) with prevention and recovery.According to same principle and use PrP sequence 114-122 as template, formerly technology shows: when synthetic one group of beta sheet destroyed peptide, 13 residue peptide (iPrP13) showed high activity (Soto, 1999, see above).Use several cell in vitro to cultivate and the interior inhibition activity of testing of body, the result spells out: might not only prevent PrP
c→ PrP
ScTransform, more meaningfully recover contagiosity PrP
ScConformation arrives and PrP
cSimilar biochemistry and configuration state (Soto etc., the manuscript of submission).
The extensive use small peptide is as the medicine in the medical science (Rao etc., C.Basava and G.M.Anantharamaiah, editor Boston:Birkhauser, 181-198 page or leaf, 1994).Yet because enzymatic degradation causes peptide drug oral bioavilability difference and acting duration weak point in the body, the development of peptide medicine is subjected to strong restrictions (Fauchere and Thurieau, Adv.Drug Res.
23: 127-159,1992).Producing the progress that proteolysis is had on the peptide analogues of hyposensitivity (as false peptide and peptide mimics) more in recent years, increasing the possibility (Fauchere and Thurieau, 1992, see above) of the useful medicine that obtains peptide structurally associated female with it.Improve peptide the stability of protease has not only been increased the half life of described compound in blood circulation, and increase its ability of on varying level, being transported or absorbing (comprising intestinal absorption and blood-brain barrier permeability), because transhipment and absorb seems highly to depend on time (Fauchere and Thurieau that film or barrier are exposed to various bioactivators, 1992, see above).
Summary of the invention
The present invention can suppress the peptide for inhibiting that βZhe Die forms in the amyloid beta-peptide, and described peptide for inhibiting is that βZhe Die destroys peptide analogues, and the βZhe Die destruction peptide that can suppress the βZhe Die formation in the amyloid beta-peptide by chemical modification designs acquisition.
The described peptide of following chemical modification: (1) modifies the terminal and C end of N of described peptide; (2) change side chain, can relate to aminoacid replacement; (3) modify alpha-carbon atom, comprise methylate, alkylation and dehydrogenation; (4) replace the L-residue with the D-residue, change chirality; (5) cyclisation end to end; (6) introduce amido link and replace, promptly change the atom that participates in peptide (or acid amides) key.
The present invention also comprises can suppress the peptide for inhibiting that amyloidosis correlation prion PrP protein conformation changes, described peptide for inhibiting is that βZhe Die destroys peptide analogues, and the βZhe Die destruction peptide that can suppress the variation of amyloidosis correlation prion PrP protein conformation by chemical modification designs acquisition.
In addition, the present invention includes peptide mimics with following array structure:
In another embodiment, described peptide mimics has following structure:
In yet another embodiment, described peptide mimics has following structure:
The present invention also comprises and is used to prevent, treat or detect the obstacle relevant with following composition or the method for disease: be folded into amyloid or the sedimental paraprotein of amyloid sample or it has the precursor of pathology beta sheet structure.
The accompanying drawing summary
Fig. 1 is used for the peptide bond of peptide modification and the schematic diagram of potential target site.
The pharmacokinetics that the 11 residue beta sheets that Fig. 2 has described the Alzheimer amyloidosis destroy peptide mortifiers (Seq.RDLPFYPVPID) when adopting its natural L configuration and non-natural D-form.
Fig. 3 A and Fig. 3 B are respectively the three-dimensional structure diagrams that the Alzheimer's beta sheet destroys peptide iA β 5 and prion beta sheet destruction peptide iPrP13.
Fig. 4 a has shown bioavilability and the stability that iA β 5 is relevant with the time with Ac-iA β 5-Am respectively with Fig. 4 b.
Fig. 5 a provide with the figure of the A β 1-40 of various other peptide incubations relatively.
Fig. 5 b is the figure of the relation of amyloid formation and Ac-iA β 5-Am concentration.
Fig. 5 c is the figure of the relation of amyloid formation and iA β 5 concentration.
Fig. 6 has shown a model, and 83% deposition is decomposed in its midventricle district, and 30% amyloid spot decomposes in the amygdaloid nucleus.
Detailed Description Of The Invention
In the present invention, to produce for using (preferably oral giving) more stable derivative in the body, improve bioavilability and the stability of peptide for inhibiting by the female peptide of chemical modification. The β-pleated sheet that described peptide for inhibiting can suppress amyloid beta peptide forms. In addition, described peptide for inhibiting is that β-pleated sheet destroys peptide analogues, and the β-pleated sheet destruction peptide that can suppress the formation of amyloid beta-peptide β-pleated sheet by chemical modification designs acquisition.
The present invention also comprises the peptide for inhibiting that the prion PrP protein conformation that can suppress to relate to amyloidosis changes, described peptide for inhibiting is that β-pleated sheet destroys peptide analogues, can suppress to relate to β-pleated sheet that the prion PrP protein conformation of amyloidosis changes by chemical modification and destroy peptide and design acquisition.
In Fig. 1, shown the vague generalization peptide backbone, wherein highlighted the possible target of chemical modification. Possible target comprises following: (1) modifies the terminal and C end (target a and target b) of N of described peptide; (2) change side chain (target c), this is usually directed to 49-Phe ,82-Ser,115-Arg,144-Met,145-Asn ,161-Arg,169-Met Human Connective tissue growth factor; (3) modify alpha-carbon atom (target d), comprise methylate, alkylation and dehydrogenation; (4) replace the L-residue with the D-residue, change chirality; (5) end to end cyclisation; (6) introduce amido link and replace (target e), namely change the atom that participates in peptide (or acid amides) key. Rear a kind of derivative is called as false peptide or amido link substitute.
Native peptides usually is subjected to the synergy of selectivity endopeptidase and non-specific exopeptidase and degrades. Endopeptidase usually is present in tissue and the cellular compartment, peptide is transformed into the fragment of two or more non-activities. Exopeptidase generally is present among blood and the peripheral organ, and complete peptide or their segment degradation are become amino acid in groups, and therefore peptide is disappeared from blood circulation. Free amine group group or carboxylic group in the exopeptidase identification polypeptide. Therefore, modifying these groups usually weakens or has eliminated the exopeptidase degraded. The peptide cyclisation causes lacking the free terminal group end to end, also therefore minimizes the cutting of exopeptidase. On the other hand, endopeptidase identification participates in the atom of amido link. Therefore, amido link replaces the degradation that can obviously reduce endopeptidase. Modify alpha-carbon atom and usually obtain same effect. Because great majority (if not all) exopeptidases and endopeptidase are stereospecific, so replace the stability that natural L-amino acid causes obviously increasing peptide with the D-stereoisomer. At last, peptide mimics has complete resistance to PD usually, and usually can orally give.Design beta sheet by the chemical modification leader peptide and destroy peptide analogues
From 5 residue alzheimer's peptide for inhibiting (iA β 5, Seq.LPFFD-also is expressed as Leu Pro Phe Phe Asp) and 13 residue prion peptide for inhibiting (iPrP13, Seq. DAPAAPAGPAVPV-also is expressed as Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val) beginning, design modification as mentioned below. Use is by synthetic peptides that uses in the present invention of standard method open and incorporated herein by reference such as Bergmann. (Bergmann ﹠ Zervas, Berichte der Deutschen Chemischen Gesellschaft (1932)65：1192-1201)
A) modify the terminal and C end of N.Terminated acetylated or the deamination of N is given the protection to many aminopeptidases digestion, and the existence that replaces the acid amides of C terminal carboxyl groups or alcohol prevents from the cutting of several carboxypeptidases to comprise the cutting of Carboxypeptidase A and protaminase.The peptide sequence of change that comprises above-mentioned modification is as follows, and wherein ac is acetylization, and am is amidatioon, and des is a deamination, and alc is alcoholization.
Alzheimer's Inhibitors The prion mortifierac-Leu Pro Phe Phe Asp-am ac-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-amdes-Leu Pro Phe Phe Asp-am des-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-amac-Leu Pro Phe Phe Asp-alc ac-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-alcdes-Leu Pro Phe Phe Asp-alc des-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-alc
B) change side chain.Alpha-non-natural amino acid exists increases stabilized peptide usually.In addition, at least a alpha-non-natural amino acid (α-An Jiyidingsuan or Aib) has applied significant restriction to the pattern peptide, lowers their conformation flexibility.Specifically, in beta sheet pattern peptide, mix the destruction fully that Aib causes this structure.The described activity of the beta sheet blocking activity of Aib and the natural residue proline that is used as the beta sheet retarding agent in peptide quite or even higher.Therefore, introduce the stability and the inhibition activity of Aib expection can the enhancing simultaneously peptide.
Alzheimer's Inhibitors The prion mortifierLeu Aib Phe Phe Asp Asp Ala Aib Ala Ala Aib Ala Ala Aib Ala Gly Aib Ala Val Aib Val
C) modify alpha-carbon atom.It is alpha-methylated improving the most frequently used α of stabilized peptide-carbon modification.In addition, show: replace the hydrogen atom that connects Phe, Val or Leu alpha-carbon atom and help adopting β-crooked conformation, the utmost point is unfavorable for forming the beta sheet structure.According to the present invention, can strengthen stability and effectiveness to the expection that methylates of these residues in the peptide for inhibiting.
Alzheimer's Inhibitors(Me) Leu Pro Phe Phe AspLeu Pro (Me) Phe Phe AspLeu Pro Phe (Me) Phe Asp (Me) Leu Pro (Me) Phe (Me) Phe Asp
The prion mortifierAsp Ala Pro Ala Ala Pro Ala Gly Pro Ala (Me) Val Pro ValAsp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro (Me) ValAsp Ala Pro Ala Ala Pro Ala Gly Pro Ala (Me) Val Pro (Me) Val
D) change chirality.Replace the remarkable resistance that increases proteolytic degradation of natural L-residue with the D-enantiomter.Confirmed that 11-residue beta sheet destroys introducing D-residue increase stability in the peptide (iA β 1).Studies show that in the body: peptide degraded fast in rat plasma with native sequences.In fact, about 90% iA β 1 degrades in a few minutes after intravenous injection.On the contrary, all residues are not almost degraded after 15 minutes in injection with iA β 1 derivative that the D form exists.For detecting, use the described peptide of standardization program radioiodination.Behind bolus injection in the rat vein, by using trichloroacetic acid precipitation, the assessment stabilized peptide.Also analyse quantitative complete peptide by ply of paper.Like this, compound of the present invention comprises: comprise iA β 5 peptides of whole D-residues and iPrP13 peptide (being respectively Fig. 3 A and Fig. 3 B) and only terminal and C end comprises the peptide of D-residue to prevent that exopeptidase from degrading at N.Except that the latter, use the D-residue in each proline back, because it is reported that a kind of common endopeptidase cleavage site of prolyl endopeptidase that is called is after this residue.
Alzheimer's Inhibitors The prion mortifierLeu pro phe phe asp asp ala pro ala ala pro ala gly pro ala val pro valleu Pro Phe Phe asp asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro valleu Pro phe Phe asp asp Ala Pro ala Ala Pro ala Gly Pro ala Val Pro val
Indicate the D-residue with the amino acid that lowercase is represented.
E) cyclic peptide.The cyclic peptide that conformation is restricted has been represented than linear peptides better medicament material standed for, because their conformation flexibility is lower, and the resistance of exopeptidase cutting is improved.Used two kinds of alternative strategies that linear peptides is converted into cyclic peptide.A kind of strategy is to introduce cysteine residues, realizes cyclisation by forming disulfide bond; Another kind of strategy relates to the side chain additional policy of the cyclisation end to end of resin-bonded.For avoiding modification, use a kind of method in back to peptide sequence.Beta sheet destroys peptide and includes the ideal sequence that is beneficial to big cyclisation, because owing to proline can promote to turn back and Cheng Huan, so it is the constituent of many natural existence or synthetic cyclic peptide.
Alzheimer's Inhibitors The prion mortifier 
F) false peptide.False peptide or amido link substitute are meant the peptide of some (or owning) peptide bonds that comprise chemical modification.Amido link replaces common following expression: keep amino acid name according to side chain, and use and be called "
Square brackets " nomenclature, point out the change that between alpha-carbon atom, takes place.
For example, term Ala
[CH2CH2] Gly is meant part NH
2CH (CH
3) CH
2CH
2CH
2CO
2H.Following table 2 has been described several amido link substitutes.
Table 2. some amido link substitute and characteristics thereof
| Substitute | Characteristic |
| ????CH 2 | Short, pliable and tough |
| ????CH 2CH 2 | Pliable and tough, hydrophobic |
| ????CH＝CH | Rigidity, hydrophobic |
| ????C≡C | Unusual rigidity |
| ????CH 2NH | Pliable and tough, hydrophilic |
| ????COCH 2 | Pliable and tough, hydrophilic |
| ????CH 2S | Pliable and tough, hydrophobic |
| ????CH 2SO 2 | Rigidity, hydrophilic more |
| ????NHCO | Rigidity, hydrophilic |
Wherein the part see the native peptides analog (as
[CHOH],
[CSNH],
[COO]), and other synthetic.Introduce the acid amides substitute and not only reduce the peptide degraded, and can significantly change some chemical-biological activities, especially the conformation flexibility and the hydrophobicity of described peptide.May increase the conformation flexibility can help mortifier is introduced A β and PrP binding site.On the other hand, because the interaction that amyloid generates between albumen and the described mortifier seems to depend on to a great extent hydrophobic interaction, therefore increase hydrophobic amido link and be substituted with and strengthen affinity, therefore strengthen the effectiveness of described mortifier.In addition, hydrophobicity strengthens the film of striding that also may strengthen described peptide transports, and therefore improves barrier (blood-brain barrier and intestines barrier) permeability.Therefore, be synthesis of pseudopeptides, using increases flexible and hydrophobic amido link replacement, as
[CH
2CH
2] and
[CH
2S].The amido link that needs to replace is those amido links that are positioned at the peptide end, to prevent the exopeptidase degraded, and be positioned at each proline amido link afterwards, because it is reported that an a kind of common endopeptidase cleavage site that is called prolyl endopeptidase appears at after this residue.Other amido link that needs protection is studied decision by experiment, and research relates to the analysis that beta sheet is destroyed peptide degraded in blood plasma and tissue.
Alzheimer's InhibitorsLeu ψ [CH
2CH
2] Pro ψ [CH
2CH
2] Phe Phe ψ [CH
2CH
2] AspLeu ψ [CH
2S] Pro ψ [CH
2S] Phe Phe ψ [CH
2S] Asp
The prion mortifierAsp ψ [CH
2CH
2] Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala Gly Pro ψ [CH
2CH
2] Ala Val Pro ψ [CH
2CH
2] ValAsp ψ [CH
2S] Ala Pro ψ [CH
2S] Ala Ala Pro ψ [CH
2S] Ala Gly Pro ψ [CH
2S] Ala Val Pro ψ [CH
2S] Val
G) some modifications mix.By the peptide medicinal property in selling and study on the examination market, can clearly realize that great majority successfully are stable at proteoclastic peptide mixing and exist several types mentioned above to modify.Consider that many different enzymes relate to the peptide degraded, this conclusion is significant.Following structure comprises the various combinations of dissimilar chemical modifications.
Alzheimer's InhibitorsAc-Leu Pro ψ [CH
2CH
2] Phe Phe Asp-AmAc-Leu Pro ψ [CH
2S] Phe Phe Asp-Am (Me) Leu Pro ψ [CH
2CH
2] Phe Phe Asp-Amleu Pro ψ [CH
2CH
2] Phe Phe aspleu Pro ψ [CH
2S] Phe Phe aspAc-Leu Aib Phe Phe Asp-Am (Me) Leu Aib Phe Phe Asp-AmLeu Pro ψ [CH
2CH
2] Phe Phe asp
Ac-Leu pro Phe Phe Asp-AmAc-Leu Pro ψ [CH
2CH
2] Phe phe Asp-AmAc-Leu Pro ψ [CH
2S] Phe Phe Asp-AmAc-Leu Pro ψ [CH
2CH
2] Phe (Me) Phe Asp-AmAc-Leu Pro ψ [CH
2CH
2] Phe (Me) Phe aspAc-Leu Pro phe Phe Asp-AmAc-Leu Pro (Me) Phe phe Asp-Amleu Pro ψ [CH
2CH
2] Phe phe aspleu Pro (Me) Phe phe aspAc-Leu Aib Phe phe Asp-Am prion mortifier Ac-Asp Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala Gly Pro ψ [CH
2CH
2] Ala Val Pro Val-Amasp Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala Gly Pro ψ [CH
2CH
2] Ala Val Pro valAc-Asp Ala Pro ψ [CH
2S] Ala Ala Pro ψ [CH
2S] Ala Gly Pro ψ [CH
2S] Ala Val Pro Val-Amasp Ala Pro ψ [CH
2S] Ala Ala Pro ψ [CH
2S] Ala Gly Pro ψ [CH
2S] Ala Val Pro valAc-Asp Ala Aib Ala Ala Aib Ala Gly Aib Ala Val Pro Val-AmAc-Asp Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala Gly Pro ψ [CH
2CH
2] Ala Val Pro (Me) ValAc-Asp Ala pro Ala Ala Pro ψ [CH
2CH
2] Ala Gly pro Ala Val Pro Val-Amasp Ala Pro ψ [CH
2CH
2] Ala Ala pro ψ [CH
2CH
2] Ala Gly Pro ψ [CH
2CH
2] Ala Val Pro (Me) Valasp Ala Aib Ala Ala Pro ψ [CH
2CH
2] Ala Gly pro Ala Val Pro (Me) Valasp Ala Aib Ala Ala Pro ψ [CH
2S] Ala Gly pro Ala Val Pro (Me) Valasp Ala Pro ψ [CH
2S] Ala Ala Pro ψ [CH
2S] Ala Gly Pro ψ [CH
2S] Ala Val Pro (Me) ValAc-Asp Ala Aib Ala Ala Pro ψ [CH
2CH
2] Ala Gly Aib Ala Val Pro (Me) Val
Ac-Asp Ala Pro ψ [CH
2S] Ala ala Pro ψ [CH
2S] Ala gly Pro ψ [CH
2S] Ala (Me) Val Pro Val-AmAc-Asp Ala Aib ala Ala Pro ψ [CH
2CH
2] Ala Gly pro Ala Val Pro (Me) Valasp Ala Aib Ala Ala Pro ψ [CH
2CH
2] Ala Gly Aib ala Val Pro Val-AmAc-Asp Ala pro Ala Ala Pro ψ [CH
2CH
2] Ala gly pro Ala (Me) Val Pro Val-Amasp Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala gly Pro ψ [CH
2CH
2] Ala val Pro valAc-Asp Ala pro Ala ala Aib Ala gly pro Ala (Me) Val Pro Val-AmAsp Ala pro Ala Ala Pro ψ [CH
2CH
2] Ala Gly pro Ala Vai Pro ValAsp Ala Aib Ala Ala Pro ψ [CH
2CH
2] Ala Gly Aib Ala (Me) Val Pro Val
The another kind of method of improving stability, also producing oral activated compound is to produce peptide mimics.Peptide mimics is the bioactive molecule of simulating peptide, but no longer is peptide on chemical nature.Sometimes part is the molecule of peptide to use the term peptide mimics to be described in essence, and as false peptide, half peptide or peptoid, but the definition of strict definition and use in the present invention is the organic molecule that no longer contains any peptide bond.Peptide mimics is not the derivative of female peptide, but in the 26S Proteasome Structure and Function characteristic of chemically synthesizing and attempting simulating peptide again.The appropriate design of peptide mimics need be for the enough understandings of the pharmacophoric group of being responsible for described peptide activity and the detailed structure information of described peptide.Target is to use its assembling organic formwork to re-construct the locus of pharmaceutical active group.The selection of template is important, and necessary consideration is big or small and flexible based on described peptide conformation model.
Design destroys the peptide mimics of peptide characteristic in order to the simulation beta sheet
The appropriate design of peptide mimics need be for the enough understandings of the chemical group of being responsible for described peptide activity and the detailed structure information of described peptide.Target is to use its assembling organic formwork to re-construct the locus of pharmaceutical active group.The selection of template is important, and necessary consideration is big or small and flexible based on described peptide conformation model.According to the research that the different beta sheets that have the single amino acid replacement is destroyed the peptide sequence activity, determined the key residue of inhibitory action.In addition, main alzheimer's beta sheet destroys the three-dimensional structure or the modeling of peptide and prion beta sheet destruction peptide (Fig. 3 A and Fig. 3 B), has perhaps tested definite.The program that uses a computer ICM, the 5-residue mortifier modelling that A β fibrillation is formed by energy minimization and Monte Carlo simulation.Use the experimental structure of having calculated the 13-residue mortifier of prion protein conformational change of 2D-NMR.
As described in up-to-date summaries such as Joachim Gante and Iwao Ojima, there are many methods to be used for designing and synthetic peptide mimics, described document is attached to herein by reference.
Below the peptide mimics of Xian Shiing is represented another aspect of the present invention.
Alzheimer's Inhibitors The prion mortifier
The latter (PMiPrP5) is a kind of shorter and more easily synthetic molecule, and it comprises chemical active radical and is the analog that 5 residue prion beta sheets destroy peptide.
Be rich in the relevant obstacle of the precursor of pathogenic beta sheet or the method for disease as prevention or treatment and amyloid or amyloid sample sediments or its, effective dose compound of the present invention can be needed the recipient of described compound, described recipient can be the mankind or animal.Equally, the method that detects such obstacle or disease also comprises the designed compound that gives effective dose, to make combining or manifesting with combining of its precursor of described compound and fibrillation deposition by well-known imaging technique.
Term used herein " prevention " recipient illness as Alzheimer's or other amyloidosis sexual dysfunction, relates to before described disease clinical episodes and gives described compound according to the present invention." treatment " relates to give described protectiveness compound after described seizure of disease.For example, after obstacle or disease generation, successfully give " treatment " of compound formation of the present invention to described disease.The animal doctor that the present invention can be used for human treatment and animal uses.
Can be by any method afford compound of the present invention that reaches its set purpose, preferably orally give.For example, can give, include but not limited in subcutaneous route, intravenous route, intradermal routes, the muscle in approach, the peritonaeum in approach, the brain approach in approach, the nose, oral route, through skin approach or cheek approach by the outer approach of multiple different stomach and intestine.It can be bolus injection or infusion progressively within a certain period of time that stomach and intestine give outward.
The typical scenario of the illness that prevention, inhibition or treatment are relevant with amyloid or amyloid sample sediments comprises: (1) gives the described compound of high concentration of potion or two doses of effective dosies, concentration range is 0.5 to 10mg, more preferably 0.5 arrive 5mg, or (2) within a certain period of time, comprise that some months arrived in the time in several years, multi-agent gives the described compound of low concentration of effective dose, and concentration range is 10-10,000 μ g is more preferably 50-500 μ g.
Certainly, the dosage that is given depends on recipient's age, sex, health and body weight, type (if any), the therapeutic frequency for the treatment of simultaneously and the character of the effect that will reach.Give each treatment required accumulated dose by multi-agent or single agent." effective dose " is meant the compound concentration that can reach following effect: slow down or suppress the formation of amyloid or amyloid sample sediments or its pathogenic beta sheet precursor, or decompose preformed fibrillation deposition.Such concentration can be determined by those skilled in the art are conventional.Those skilled in the art also know: dosage will depend on the stability of institute's administered compound.Need multi-agent to give than unstable compounds.
Be used for the preparation that stomach and intestine give outward and comprise the aseptic aqueous solution and non-aqueous solution, suspension and emulsion, described preparation can comprise adjuvant known in the art and excipient.Also can prepare Pharmaceutical composition such as tablet and capsule according to conventional method.
The Pharmaceutical composition that comprises The compounds of this invention comprises all compositions that wherein comprise the described compound of effective dose that reaches set objective.In addition, described Pharmaceutical composition can comprise suitable pharmaceutical carriers, is processed into excipient and adjuvant at pharmaceutically available preparation comprising helping reactive compound.Suitable pharmaceutically acceptable carrier is well-known in this area, and for example at a canonical reference book Gennaro of this area, Alfonso edits, Remington ' s Pharmaceutical Science, the 18th edition 1990, Mark PublishingCo., Easton has description among the PA.
Can be according to administering mode and described compound dissolution degree and stability, routine is chosen in pharmaceutically acceptable carrier.For example, the preparation that intravenous gives can comprise aseptic aqueous solution, and described aseptic aqueous solution can also comprise buffer, thinner and other suitable additive.
Be used for the aqueous solution that appropriate formulation that stomach and intestine give comprises reactive compound as described in the water lysotype (as water soluble salt) outward.In addition, can give described reactive compound suspension as suitable oily injection suspensions.Suitable lipophilic solvent or carrier comprise fat oil such as sesame oil or synthetic fatty acid ester such as ethyl oleate or triglyceride.Liquid drugs injection suspension can comprise the material that increases described suspension viscosity, and described material comprises for example sodium carboxymethylcellulose, sorbierite and/or glucan (destran).Described suspension can also be chosen wantonly and comprise stabilizing agent.
By giving Pharmaceutical composition of the present invention, can treat or prevent to be rich in the paraprotein of pathogenic precursor of beta sheet relevant obstacle or disease and to include but not limited to being folded into amyloid or amyloid sample sediments or being folded into described deposition: Alzheimer's, FAF, Down syndrome, other amyloidosis sexual dysfunction, human prion is sick as kuru, Creutzfeldt-Jacob disease (CJD), Gerstmann-Strausslet-Scheinker syndrome (GSS), prion correlation human nerve's degenerative disease and animal prion disease such as itch disease, spongiform encephalopathy, the chronic wasting disease of TME and mule deer and elk.
Embodiment
Peptide is their quick proteolytic degradation in biofluid and tissue as a major defect of medicine.In experiment in vitro, iA β 5 (Seq.LPFFD-this paper also is described as LeuPro Phe Phe Asp) is very rapidly degraded behind external and fresh human plasma incubation.Described in Fig. 4 a, have under the situation of blood plasma that 50 percent iA β 5 peptides disappear after about 5 minutes.Owing to can not identify any metabolism fragment, therefore seem to degrade and mainly finish by nonspecific exopeptidase as the proteolytic digestion result.The support that this conclusion is subjected to finding below: amino terminal and the carboxyl terminal (form Ac-iA β 5-Am-this paper and be also referred to as Ac-Leu Pro Phe Phe Asp-Am) by acetylization and amidatioon protection peptide significantly increases this peptide in external stability respectively.Shown in Fig. 4 b, it is stable above 24 hours that terminal protection modified peptides of the present invention (Ac-iA β 5-Am) keeps in human plasma.(the external also slow metabolism in human and rat liver microsome of described modified peptides wherein at 37 ℃ of incubations after 1 hour, has 81.5% and 76.3% peptide to be kept perfectly respectively in human tissue homogenate and the rat tissue's homogenate.)
Other in vitro study shows: Ac-iA β 5-Am and iA β 5 form and similar activity are arranged (see Fig. 5 a), its effect is followed the active similar dose dependent to the unmodified peptide, shown in Fig. 5 b and Fig. 5 c suppressing amyloid.Get back to Fig. 5 a, can see with Boc and modify the external activity that the N end also keeps iA β 5 to show, and several uncorrelated peptide of same concentrations (CP1:VHVSEEGTEPA, CP2:GYLTVAAVFRG, CP10:ISEVKMDAEF) or short A β fragment (as A β 18-21, A β 1-16) generate not effect for fibrillation, perhaps may slightly increase amyloid by mixing fibrillation and form.
Be assessment Ac-iA β 5-Am effect in vivo, we have used a rat model, and wherein the A β 1-42 that does not assemble by intracerebral injection induces amyloidosis.After some times, described peptide is assembled in rat brain, causes forming an amyloid sample deposition in injection site.These pathologies have the dyeing identical with the alzheimer's amyloid plaque (Congo red birefringence and thioflavine S combination) and translucent (fibrillar structure under electron microscope) characteristic, induce some and the similar brain damage of observed brain damage in the AD brain, comprise that neuron shrinkage widely, astrocytosis and microglia cell activate.Use this model, shown before us that unprotected iA β 5 of common injection and A β 1-42 cause suppressing 50% starch spot formation, and i.c. injection iA β 5 causes 67% preformed deposition to be decomposed in the animal that comprises amyloid plaque.(Sigurdsson, E.M., Permanne, B.Soto, C., Wisniewski, T.﹠amp; Decompose .J. Neuropath.Exp.Neurol.59:11-17 in the body of amyloid beta in the Frangione, B. (2000) rat brain-deposition).In the former experiment, directly inject unprotected peptide in the brain district that amyloid was positioned at.In this experiment, amyloid beta 5 peptides are injected into the amygdaloid nucleus of rat.After 7 days, promptly amyloid deposition is completed into the required time, uses the ALZET infusion pump that is connected to telocoele, and infusion contains the 100 μ L solution of 13mg/ml Ac-iA β 5-Am in three weeks.Put to death animal and the situation that exists by amyloid beta deposition in the immunohistochemical analysis brain.In this model, obtain fine and close amyloid plaque in the place (amygdaloid nucleus) of the solution that deposits the described A of containing β 1-42, the whole catheter trajectory in the zone of the more close ventricles of the brain is observed several littler amyloid depositions (Fig. 6, left figure) simultaneously.The result shows: the described peptide of infusion makes 30% preformed amyloid plaque decomposition in the amygdaloid nucleus, and 83% deposition is decomposed near the ventricles of the brain.Experimental arrangement
The analyzed in vitro of stabilized peptide.The 1 μ g/ μ l aqueous solution of preparation peptide.The described peptide solution of 20 μ l is diluted in the fresh human plasma of 80 μ l.This solution is 37 ℃ of following incubation different time length, by adding the complete mixture cessation reaction of protease inhibitors.Cold ethanol (mixing/MeOH, 4/5, v/v) in-20 ℃ one hour, precipitate most of plasma proteins (not having peptide).Centrifugal (10000g, 10 minutes, 4 ℃) make the protein precipitation deposition.Contain 5 times of the supernatant vacuum concentration of peptide, separate by reversed-phase HPLC.Measurement is corresponding to the peak area of complete peptide, and compares with the equal sample with the blood plasma incubation not.
Active external test.Discharge by the fluorescence that is incorporated into the fibriilar thioflavine T of amyloid (ThT), the qualitative assessment amyloid forms.At 0.1M Tris, branch things such as the A β for preparing among the pH7.4 were lacking or are existing under the situation of variable concentrations iA β 5 and derivative thereof with concentration 0.5mg/ml, in 37 ℃ of incubations 7 days.At the terminal point of incubation period, add the 50mM glycine, pH9.2 and 2 μ M ThT reach the final volume of 2ml.Use Perkin Elmer LS50B type sepectrophotofluorometer, exciting 435nm and emission 485nm place to measure fluorescence.
Make the animal model of the AP deposition of requiring mental skill carry out research in the body.Male Fischer-344 rat is heavy 250-300g when arriving, the 3-4 monthly age.2 rats of every cage keep 12 hours light dark periods, and ad libitum access and drinking-water make them shake down 2-3 week before operation.Under yellow Jackets (in the 50mg/kg, peritonaeum) anesthesia, undergo surgery.In case behind the anesthetized animal, hypodermic injection atropine sulfate (0.4mg/kg) and ampicillin sodium salt (50mg/kg).A β 1-42 is dissolved in methyl-sulfoxide (DMSO), is diluted with water to 16.7% DMS.Use the Kopf stereotaxic apparatus, the front tooth bar is set to 3.3mm under the biauricular line, and bilateral injection 5.0nmol A β 1-42 goes into two amygdaloid nucleus of animal.Rule of thumb determine the injection coordinate (AP-3.0, ML scholar 4.6DV-8.8) that begins to measure from anterior fontanelle and cranium surface according to the collection of illustrative plates of Paxinos and Watson.Use CMA/100 microsyringe pump, injection 3.0 μ l volumes (flow velocity 0.5 μ l/ minute) in 6 minutes.Injection rear tube original position kept 2 minutes, extracted 0.2mm then and kept 3 minutes, slowly extracted conduit after 5 minutes.The animal postoperative places on the heating pad up to recovering righting reflex.Be the effect of assessment Ac-i β 5-AM, perform the operation for the first time one week the back animal carried out second time perform the operation, wherein an ALZET infusion pump is connected to the ventricles of the brain according to manufacturer's indication.The peptide of 1.3mg altogether in 3 time-of-weeks in the transmission 100 μ lPBS/10% DMSO is to telocoele.After this, the excessive yellow Jackets of aortic perfusion (150mg/kg, intraperitoneal injection) are put to death rat.For carrying out histologic analysis, carry out the crown section of brain (40 μ m) continuously ,-20 ℃ of preservations are until dyeing in ethylene glycol antifreeze.As Soto, C., Sigursson, E., Morelli, L., Kumar, R.A., Castano, E.M. and Frangione, B. (1998) beta sheet destroys peptide and suppresses fibrillation generate in amyloidosis rat brain model: Alzheimer's is treated described in the problem .Nature med.4:882-886, with anti-A β 1-42 antibody staining histologic section.Use the imaging analysis system to determine the size of amyloid deposition.Analyze with dual factors ANOVA, carry out subsequently comparison with the Newman-Keuls multiple range test then, analyze described data.Use non-matching sided t-check analysis brain always to deposit.
After fully describing the present invention, those skilled in the art know: do not need the experiment expected, just can be in the broad range of equal parameter, concentration and condition the same scheme of enforcement, and can not depart from the spirit and scope of the present invention.
Though described the present invention with regard to its particular, people will recognize and can further change the present invention.The application comprises all such the present invention change, uses and changes embodiment: follow principle of the present invention generally, and the included content different with the disclosure of invention belongs to the known in the art or conventional practice of the present invention and belong to the above essential characteristic of following appended claims statement.
The list of references that all this paper quote, comprise journal articles or summary, the disclosed or corresponding U.S. or foreign patent application, the U.S. of having authorized or foreign patent or any other list of references, all intactly be attached to herein by reference, be included in all data, table, figure and text in the incorporated by reference document.In addition, the full content of the list of references of being quoted in the list of references that this paper quoted also intactly is attached to herein by reference.
Reference to known method step, conventional method step, known method or conventional method is to recognize that in no instance any aspect of the present invention, description or embodiment disclose, point out or propose in pertinent literature.
General features of the present invention has so fully been disclosed for the description of particular in the front, so that other people can needn't too much test by the knowledge of using in this area (content that comprises the list of references that this paper quotes), just can easily the various application of described particular be changed and/or change, and do not depart from general plotting of the present invention.Therefore, according to instruction and the guidance that this paper proposed, such change and change will be included in being equal in embodiment meaning and the scope of disclosed embodiment.Certainly, word and the term of this paper are used to describe rather than limit the present invention, so the word of this specification and term should be by the technical staff according to the instructions of this paper statement with instruct and explain in conjunction with those skilled in that art's knowledge.
Claims (19)
1. one kind can be suppressed the peptide for inhibiting that amyloid beta-peptide forms βZhe Die, and it is can suppress βZhe Die that amyloid beta-peptide forms βZhe Die by chemical modification to destroy the βZhe Die that peptide designs acquisition and destroy peptide analogues.
2. the peptide for inhibiting of claim 1, it is 5 residue Alzheimer peptide for inhibiting iA β, 5 (Seq.Leu-Pro-Phe-Phe-Asp) that wherein said βZhe Die destroys peptide.
3. the peptide for inhibiting of claim 2, wherein said chemical modification realizes by being selected from following method: the terminal and C end of N that changes described Alzheimer peptide for inhibiting iA β 5; At least one residue that replaces described Alzheimer peptide for inhibiting iA β 5 with α-An Jiyidingsuan (Aib); The alpha-carbon atom of described Alzheimer peptide for inhibiting iA β 5 at least one residue methylates; At least one the L-enantiomter residue that replaces described Alzheimer peptide for inhibiting iA β 5 with D-enantiomter residue, make described Alzheimer peptide for inhibiting iA β 5 form cyclisation end to end, replace amido link among the described Alzheimer peptide for inhibiting iA β 5 with the amido link substitute; And their combination.
4. the peptide for inhibiting of claim 3 is wherein by being selected from the terminal and C end of N that following method changes described Alzheimer peptide for inhibiting iA β 5: acetylization, amidatioon, deamination, alcoholization and their combination.
5. the compound of claim 4, wherein peptide for inhibiting is selected from: ac-Leu Pro Phe PheAsp-am, des-Leu Pro Phe Phe Asp-am, ac-Leu Pro Phe Phe Asp-alc and des-Leu Pro Phe Phe Asp-alc.
6. the peptide for inhibiting of claim 5, wherein said peptide for inhibiting is ac-Leu Pro Phe PheAsp-am.
7. the peptide for inhibiting of claim 3, wherein said peptide for inhibiting is selected from: Leu Aib Phe Phe Asp; (Me) Leu Pro Phe Phe Asp; Leu Pro (Me) Phe Phe Asp, Leu ProPhe (Me) Phe Asp; (Me) Leu Pro (Me) Phe (Me) Phe Asp, leu pro phe phe asp, leu Pro Phe Phe asp, leu Prophe Phe asp, Leu ψ [CH
2CH
2] Pro ψ [CH
2CH
2] Phe Phe ψ [CH
2CH
2] Asp; Leu ψ [CH
2S] Pro ψ [CH
2S] PhePhe ψ [CH
2S] Asp; Ac-Leu Pro ψ [CH
2CH
2] Phe Phe Asp-Am; Ac-Leu Pro ψ [CH
2S] Phe Phe Asp-Am; (Me) Leu Pro ψ [CH
2CH
2] Phe Phe Asp-Am; Leu Pro ψ [CH
2CH
2] Phe Phe asp; Leu Pro ψ [CH
2S] Phe Phe asp; Ac-Leu Aib Phe Phe Asp-Am; (Me) Leu Aib Phe Phe Asp-Am; Leu Pro ψ [CH
2CH
2] Phe Phe asp;
Ac-Leu pro Phe Phe Asp-Am; Ac-Leu Pro ψ [CH
2CH
2] Phe phe Asp-Am; Ac-Leu Pro ψ [CH
2S] Phe phe Asp-Am; Ac-Leu Pro ψ [CH
2CH
2] Phe (Me) Phe Asp-Am; Ac-Leu Pro ψ [CH
2CH
2] Phe (Me) Phe asp; Ac-Leu Pro phe phe Asp-Am; Ac-Leu Pro (Me) Phe phe Asp-Am; Leu Pro ψ [CH
2CH
2] Phe phe asp; LeuPro (Me) Phe phe asp; Ac-Leu Aib Phe phe Asp-Am; And
8. one kind can be suppressed the peptide for inhibiting that amyloidosis correlation prion PrP protein conformation changes, and described peptide for inhibiting is can suppress βZhe Die that described amyloidosis correlation prion PrP protein conformation changes by chemical modification to destroy the βZhe Die that peptide designs acquisition and destroy peptide analogues.
9. the peptide for inhibiting of claim 8, it is 13 residue prion peptide for inhibiting iPrP13 (Seq.Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val ProVal) that wherein said βZhe Die destroys peptide.
10. the peptide for inhibiting of claim 9, wherein said chemical modification realizes by being selected from following method: the terminal and C end of N that changes described prion peptide for inhibiting iPrP13; At least one residue that replaces described prion peptide for inhibiting iPrP13 with α-An Jiyidingsuan (Aib); The alpha-carbon atom of described at least one residue of prion peptide for inhibiting iPrP13 methylates; At least one the L-enantiomter residue that replaces described prion peptide for inhibiting iPrP13 with D-enantiomter residue, make described prion peptide for inhibiting iPrP13 form cyclisation end to end, replace amido link among the described prion peptide for inhibiting iPrP13 with the amido link substitute; And their combination.
11. the peptide for inhibiting of claim 10 is wherein by being selected from the terminal and C end of N that following method changes described prion peptide for inhibiting iPrP13: acetylization, amidatioon, deamination, alcoholization and their combination.
12. the compound of claim 11, wherein said peptide for inhibiting is selected from: ac-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-am, des-Asp AlaPro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-am, ac-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala ValPro Val-alc, and des-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-alc.
13. the peptide for inhibiting of claim 10, wherein said peptide for inhibiting is selected from: Asp Ala Aib Ala Ala Aib Ala Ala Aib Ala Gly Aib Ala Val Aib Val; Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala (Me) Val Pro Val; Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro (Me) Val; Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala (Me) Val Pro (Me) Val; Asp ala pro ala ala pro ala gly pro ala val pro val; Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro val; Asp Ala Pro ala Ala Pro ala Gly Pro ala Val Pro val; Asp ψ [CH
2CH
2] Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala Gly Pro ψ [CH
2CH
2] AlaVal Pro ψ [CH
2CH
2] Val; Asp ψ [CH
2S] Ala Pro ψ [CH
2S] Ala Ala Pro ψ [CH
2S] Ala Gly Pro ψ [CH
2S] Ala Val Pro ψ [CH
2S] Val; Ac-Asp Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala Gly Pro ψ [CH
2CH
2] Ala Val Pro Val-Am; Asp Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala Gly Pro ψ [CH
2CH
2] Ala Val Pro val; Ac-Asp Ala Pro ψ [CH
2S] Ala Ala Pro ψ [CH
2S] Ala Gly Pro ψ [CH
2S] Ala Val Pro Val-Am; Asp Ala Pro ψ [CH
2S] Ala Ala Pro ψ [CH
2S] Ala Gly Pro ψ [CH
2S] Ala Val Pro val; Ac-Asp Ala Aib Ala Ala Aib Ala Gly Aib Ala Val Pro Val-Am; Ac-Asp Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala Gly Pro ψ [CH
2CH
2] Ala Val Pro (Me) Val; Ac-Asp Ala pro Ala Ala Pro ψ [CH
2CH
2] Ala Gly pro Ala Val Pro Val-Am; Asp Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala Gly Pro ψ [CH
2CH
2] Ala Val Pro (Me) Val; Asp Ala Aib Ala Ala Pro ψ [CH
2CH
2] Ala Gly pro Ala Val Pro (Me) Val; Asp Ala Aib Ala Ala Pro ψ [CH
2S] Ala Gly pro Ala Val Pro (Me) Val; Asp Ala Pro ψ [CH
2S] Ala Ala Pro ψ [CH
2S] Ala Gly Pro ψ [CH
2S] Ala Val Pro (Me) Val; Ac-Asp Ala Aib Ala Ala Pro ψ [CH
2CH
2] Ala Gly Aib Ala Val Pro (Me) Val;
Ac-Asp Ala Pro ψ [CH
2S] Ala ala Pro ψ [CH
2S] Ala gly Pro; ψ [CH
2S] Ala (Me) Val Pro Val-Am; Ac-Asp Ala Aib ala Ala Pro ψ [CH
2CH
2] Ala Gly pro Ala Val Pro (Me) Val; Asp Ala Aib Ala Ala Pro ψ [CH
2CH
2] Ala Gly Aib ala Val Pro Val-Am; Ac-Asp Ala pro Ala Ala Pro ψ [CH
2CH
2] Ala gly pro Ala (Me) Val Pro Val-Am; Asp Ala Pro ψ [CH
2CH
2] Ala Ala Pro ψ [CH
2CH
2] Ala gly Pro ψ [CH
2CH
2] Ala val Pro val; Ac-Asp Ala pro Ala ala Aib Ala gly pro Ala (Me) Val Pro Val-Am; Asp Ala pro Ala Ala Pro ψ [CH
2CH
2] Ala Gly pro Ala Val Pro Val; Asp Ala Aib Ala Ala Pro ψ [CH
2CH
2] Ala Gly Aib Ala (Me) Val Pro Val; And,
14. a peptide mimics, it has following structure:
15. a peptide mimics, it has following structure:
16. a peptide mimics, it has following structure:
17. method, this method is used to reduce and forms the amount that amyloid beta peptide is folded into the amyloid or the amyloid sample sediments of βZhe Die structure unusually or reduces the described amyloid beta peptide that has formed the βZhe Die structure that relates to, and described method is included in described amyloid beta peptide and is folded into the peptide of introducing the claim 1 of effective dose before or after the βZhe Die structure in the described amyloid beta peptide that exists unusually.
18. method, this method is used to reduce form and relates to amyloid or the amyloid sample sediments that prion Pr protein conformation changes or reduce the amount that has formed amyloid or the sedimental described prion Pr albumen of amyloid sample, and described method is included in described prion Pr albumen and described conformation change takes place forms the peptide of introducing the claim 8 of effective dose before or after the amyloid beta deposition thing in the described prion Pr albumen that exists.
19. one kind is reduced and forms amyloid or the sedimental method of amyloid sample, this method afford is selected from following peptide mimics:
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| JP (1) | JP2004513873A (en) |
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| CN101228443B (en) * | 2005-07-19 | 2013-03-27 | 米兰大学 | Method for the identification of proteins folding inhibitors |
| CN103946232A (en) * | 2011-07-07 | 2014-07-23 | 新加坡科技研究局 | Anti-amyloidogenic,alpha-helix breaking ultra-small peptide therapeutics |
| CN105745219A (en) * | 2013-09-26 | 2016-07-06 | 于利奇研究中心有限公司 | Amyloid-beta-binding peptides and the use thereof for the therapy and diagnosis of alzheimer's dementia |
| CN105764354A (en) * | 2013-10-11 | 2016-07-13 | 马来西亚棕榈油协会 | Protective effects of oil palm composition on alzheimer's disease |
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| US8003612B2 (en) | 1997-10-08 | 2011-08-23 | Proteotech Inc. | Small peptides for the treatment of Alzheimer's disease and other beta-amyloid protein disorders |
| DE10101430B4 (en) | 2001-01-13 | 2008-10-02 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Soluble cyclic analogues for the modulation of amyloidogenesis |
| AU2004203461B2 (en) * | 2002-01-31 | 2009-09-03 | Tel Aviv University Future Technology Development L.P. | Peptides Antibodies Directed Thereagainst and Methods Using Same for Diagnosing and Treating Amyloid-Associated Diseases |
| US20040052928A1 (en) | 2002-09-06 | 2004-03-18 | Ehud Gazit | Peptides and methods using same for diagnosing and treating amyloid-associated diseases |
| DE10230141B4 (en) * | 2002-07-04 | 2004-07-15 | Priontype Gmbh | Method and kit for the enrichment and detection of modified prion proteins (PrPSc) |
| AU2003271745A1 (en) * | 2002-07-08 | 2004-01-23 | Laboratoires Serono Sa | Beta-SHEET BREAKING PEPTIDES |
| JP2006520321A (en) * | 2002-12-02 | 2006-09-07 | アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ | Aza-peptide |
| EP1638517A4 (en) * | 2003-06-30 | 2010-01-06 | Univ Tel Aviv Future Tech Dev | Peptides antibodies directed thereagainst and methods using same for diagnosing and treating amyloid-associated diseases |
| US20060057673A1 (en) * | 2004-06-17 | 2006-03-16 | Liping Liu | Epitope analogs |
| WO2006090289A2 (en) * | 2005-02-28 | 2006-08-31 | Alphabeta Ab | Compounds for reducing aggregation of amyloid beta-peptide |
| EP1883627B1 (en) * | 2005-05-18 | 2018-04-18 | Pharmascience Inc. | Bir domain binding compounds |
| SG173405A1 (en) * | 2006-08-04 | 2011-08-29 | Lonza Biologics Plc | Method for predicting protein aggregation and designing aggregation inhibitors |
| MX2013005413A (en) | 2010-11-15 | 2014-02-27 | Univ Ramot | Dipeptide analogs for treating conditions associated with amyloid fibril formation. |
| MX347354B (en) * | 2011-08-17 | 2017-04-24 | Ironwood Pharmaceuticals Inc | Treatments for gastrointestinal disorders. |
| DE102013016002A1 (en) | 2013-09-26 | 2015-03-26 | Forschungszentrum Jülich GmbH | Cyclic amyloid beta-binding peptides and their use |
| KR101627106B1 (en) | 2014-03-26 | 2016-06-03 | 연세대학교 산학협력단 | polypeptide having multiple directionality and self-assembled nanostructure containing the same |
| DE102015003676A1 (en) * | 2015-03-20 | 2016-09-22 | Forschungszentrum Jülich GmbH Fachbereich Patente | Specifically A-beta species-binding peptides for the therapy and / or diagnosis of Alzheimer's dementia |
| MA53500A (en) | 2018-05-15 | 2021-08-18 | Lloyd Hung Loi Tran | THERAPEUTIC AGENT COMPOSITION AND METHOD OF USE, FOR TREATING MILD COGNITIVE DISORDER, DEPRESSION AND PSYCHOLOGICAL DISORDERS |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE69621607T2 (en) * | 1995-03-14 | 2003-01-02 | Praecis Pharm Inc | CONNECTIONS WITH AGGREGATION-MODULATING EFFECT ON THE AMYLOiD PROTEIN |
| US5948763A (en) * | 1995-06-07 | 1999-09-07 | New York University | Peptides and pharmaceutical compositions thereof for treatment of disorders or diseases associated with abnormal protein folding into amyloid or amyloid-like deposits |
| WO1998008868A1 (en) * | 1996-08-27 | 1998-03-05 | Praecis Pharmaceuticals Incorporated | MODULATORS OF β-AMYLOID PEPTIDE AGGREGATION COMPRISING D-AMINO ACIDS |
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- 2000-11-04 EP EP00976928A patent/EP1286590A4/en not_active Withdrawn
- 2000-11-04 CA CA002389041A patent/CA2389041A1/en not_active Abandoned
- 2000-11-04 EA EA200200536A patent/EA004739B1/en unknown
- 2000-11-04 KR KR1020027005797A patent/KR20020079731A/en not_active Application Discontinuation
- 2000-11-04 IL IL14939200A patent/IL149392A0/en unknown
- 2000-11-04 AU AU14635/01A patent/AU781044B2/en not_active Ceased
- 2000-11-04 WO PCT/US2000/030416 patent/WO2001034631A2/en not_active Application Discontinuation
- 2000-11-04 MX MXPA02004468A patent/MXPA02004468A/en active IP Right Grant
- 2000-11-04 JP JP2001537342A patent/JP2004513873A/en not_active Withdrawn
- 2000-11-04 CN CN00819247A patent/CN1437442A/en active Pending
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101228443B (en) * | 2005-07-19 | 2013-03-27 | 米兰大学 | Method for the identification of proteins folding inhibitors |
| CN103946232A (en) * | 2011-07-07 | 2014-07-23 | 新加坡科技研究局 | Anti-amyloidogenic,alpha-helix breaking ultra-small peptide therapeutics |
| CN103946232B (en) * | 2011-07-07 | 2017-07-21 | 新加坡科技研究局 | The ɑ spirals of anti-amyloid block extra small peptide therapy |
| CN105745219A (en) * | 2013-09-26 | 2016-07-06 | 于利奇研究中心有限公司 | Amyloid-beta-binding peptides and the use thereof for the therapy and diagnosis of alzheimer's dementia |
| CN105745219B (en) * | 2013-09-26 | 2020-10-09 | 于利奇研究中心有限公司 | Amyloid beta-binding peptides and their use for the treatment and diagnosis of alzheimer's dementia |
| CN105764354A (en) * | 2013-10-11 | 2016-07-13 | 马来西亚棕榈油协会 | Protective effects of oil palm composition on alzheimer's disease |
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| AU1463501A (en) | 2001-06-06 |
| WO2001034631A2 (en) | 2001-05-17 |
| EP1286590A2 (en) | 2003-03-05 |
| BR0015513A (en) | 2004-07-06 |
| KR20060133114A (en) | 2006-12-22 |
| IL149392A0 (en) | 2002-11-10 |
| JP2004513873A (en) | 2004-05-13 |
| KR20020079731A (en) | 2002-10-19 |
| EP1286590A4 (en) | 2005-05-11 |
| WO2001034631A3 (en) | 2002-12-27 |
| AU781044B2 (en) | 2005-05-05 |
| CA2389041A1 (en) | 2001-05-17 |
| EA200200536A1 (en) | 2002-12-26 |
| EA004739B1 (en) | 2004-08-26 |
| MXPA02004468A (en) | 2004-09-10 |
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