CN102311487B - Polypeptide, composition and the purposes of AntiHIV1 RT activity infection - Google Patents

Polypeptide, composition and the purposes of AntiHIV1 RT activity infection Download PDF

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CN102311487B
CN102311487B CN201010216187.0A CN201010216187A CN102311487B CN 102311487 B CN102311487 B CN 102311487B CN 201010216187 A CN201010216187 A CN 201010216187A CN 102311487 B CN102311487 B CN 102311487B
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glu
lys
polypeptide
trp
ile
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CN102311487A (en
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刘克良
姜世勃
史卫国
贾启燕
白玉
冯思良
蔡利锋
王潮
张沙
姜喜凤
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Institute of Pharmacology and Toxicology of AMMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/73—Fusion polypeptide containing domain for protein-protein interaction containing coiled-coiled motif (leucine zippers)
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16033—Use of viral protein as therapeutic agent other than vaccine, e.g. apoptosis inducing or anti-inflammatory
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    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

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Abstract

The invention belongs to biomedicine fields, are related to a kind of polypeptide of AntiHIV1 RT activity infection, and in particular, to Formulas I Y1‑IXb1ELXe1BB‑SXb2ELXe2BB‑IXb3EXd3Xe3BB‑Xa4Xb4EXd4Xe4BB‑Y2The salt of polypeptide shown in Formulas I, its derivative, its stereoisomer or its physiological-toxicity-free.The invention further relates to the purposes of salt relevant disease especially acquired immunodeficiency syndrome (AIDS) caused by treating or preventing HIV infection of the pharmaceutical composition of the salt containing above-mentioned Formulas I polypeptide, its derivative, its stereoisomer or its physiological-toxicity-free and Formulas I polypeptide, its derivative, its stereoisomer or its physiological-toxicity-free.

Description

Polypeptide, composition and the purposes of AntiHIV1 RT activity infection
Technical field
The invention belongs to biomedicine fields, are related to a kind of polypeptide of AntiHIV1 RT activity infection, and in particular, to more shown in Formulas I The salt of peptide, its derivative, its stereoisomer or its physiological-toxicity-free.The invention further relates to containing above-mentioned Formulas I polypeptide, its The pharmaceutical composition and Formulas I polypeptide of the salt of derivative, its stereoisomer or its physiological-toxicity-free, its derivative, it is vertical Body isomers or the salt of its physiological-toxicity-free the relevant disease especially acquired immunity caused by treating or preventing HIV infection lack Fall into the purposes of syndrome (AIDS, i.e. AIDS).
Y1-IXb1ELXe1BB-SXb2ELXe2BB-IXb3EXd3Xe3BB-Xa4Xb4EXd4Xe4BB-Y2Formulas I.
Background technology
AIDS is worldwide popular at present, brings and seriously threatens to human health.Human Mn superoxide dismutase (HIV-1) it is the main pathogens for causing AIDS to infect.Due to traditional reverse transcriptase inhibitor and protease inhibitors drug resistance Sex chromosome mosaicism becomes increasingly conspicuous so that developmental function becomes common recognition in HIV-1 life cycle novel targets drugs.HIV fusion inhibitors (HIVfusion inhibitors) is the new class inverase that viral interference enters target cell, with traditional enzyme inhibitor Difference, it is acted on extracellularly, and in the propagation of the initial link cut-out virus of infection, this is for preventing and controlling HIV-1 infection It acquires a special sense, thus as the hot spot of new mechanism inverase research.
HIV fusion inhibitor HIV-1 fusion proteins gp41 is action target, and Gp41 is that HIV-1 is mediated to melt with target cell membrane The functional protein of conjunction.HIV fusion inhibitors promote the shape of six dimeric structure of core (6-HB) of film fusion by inhibition gp41 At to inhibit cell entry target cell.T-20 is the HIV-1 fusion inhibitors of first and currently the only listing, it is 36 peptide of native sequences (being known as C peptides) derived from the functional areas HIV-1 gp41 HR2, was ratified in 2003 by FDA.T20 can be with Gp41 is combined, and to which the functional core hearty cords of Reverse transcriptase gp41 mediated fusions is configured to, blocks HIV-1 and target cell membrane Fusion process inhibits viral target cell infection.
Although the discovery of T-20 opens the frontier for controlling HIV using peptide medicament, due to itself existing one A little defects and deficiency, limit the extensive use of T20.It is drug resistance first, since T20 is derived from gp41 native sequences completely, High to the sensibility of target mutation, the mutation of target sequence single amino acids residue can cause T20 activity to reduce by 10 times, and two residual Base mutation can then make its activity reduce by 100 times.Therefore, although the native sequences of T20 maintain natural ligand to the maximum extent Structure, but also cause virus to be easy to generate drug resistance to T20 due to the high mutability of target HIV-1gp41 sequences.Secondly, T20 is easily easily degraded by proteases, and vivo biodistribution availability is low.Therefore, how to overcome drug resistance and improve enzymolysis stability, be new The Main way of generation HIV fusion inhibitors research.
Current HIV-1 peptides fusion inhibitors, are mainly based upon the optimization and transformation of active natural ligand sequence.Such as the A generation fusion inhibitor T-20, C34 etc. are the native sequences for being directly derived from gp41HR2；Second generation T1249, sifuvirtide, T1144 etc. is carried out obtained from deletion replacement to wherein nonconserved amino acid residues on the basis of native sequences.It is based on Natural ligand sequence is designed with its reasonability and feasibility, but since the height of natural origin sequence pair resistance mutation is sensitive Property, this design has certain limitation.
For these reasons, present inventors have proposed the HIV-resistant activity peptides of the non-natural derived sequence based on target construction Design philosophy：Based on the three-dimensional crystalline structure of target gp41 HR1 spiral tripolymers, the design and rational side of appliance computer auxiliary Method, from the beginning design Non-native sequences alpha helical peptides, simulate the activity conformation of natural C peptides, with target combine and generation it is corresponding give birth to Thus object function designs the HIV-resistant activity polypeptide of brand new.Utilize Non-native sequences and the complete non-homology of native sequences Feature explores the new approaches for inhibiting drug resistance.The content of present invention is completed therefrom.
Invention content
Purpose of the present invention is to design the AntiHIV1 RT activity of new complete Non-native sequences to infect polypeptide, and have and native sequences phase When or higher inhibition HIV infection activity, while T20 drug resistance HIV strains can be inhibited.
One aspect of the present invention be related to polypeptide shown in Formulas I, its derivative, its stereoisomer or its without physiology poison The salt of property,
Y1-IXb1ELXe1BB-SXb2ELXe2BB-IXb3EXd3Xe3BB-Xa4Xb4EXd4Xe4BB-Y2Formulas I
Wherein,
Y1For 7-14 amino acid residue being combined with HIV-1 gp41 N-trimer surface hydrophobics pocket region Peptide sequence or micromolecular compound or Y1Missing；
Xb1、Xb2、Xb3It is separately the natural or non-natural acidic amino acid or hydrophilic amino of D types or L-type Acid；
Xb4For D types or the natural or non-natural acidic amino acid or hydrophobic amino acid of L-type；
Xe1、Xe2、Xe3、Xe4It is separately the natural or unnatural hydrophobic acidic amino acid of D types or L-type；
Xd3、Xd4It is separately the natural or unnatural hydrophobic or hydrophilic amino acid of D types or L-type；
Xa4For D types or the natural or non-natural hydrophilic amino acid of L-type；
B is the natural or non-natural basic amino acid of D types or L-type；
Y2For the long-chains more than peptide sequence of the 7-14 amino acid residue acted on adipose membrane, cholesterol or 6 carbon atoms Aliphatic acid or Y2Missing.
Term used herein " stereoisomer " refers to D- the or L- spatial configurations of Formulas I polypeptide.
In one embodiment of the invention, Y1Sequence chosen from the followings：WMEWDRE-(SEQID NO：35)、 TWMEWDRE-(SEQ ID NO：36)、MTWMEWDRE-(SEQ ID NO：37)、NMTWMEWDRE-(SEQ ID NO：38)、 NNMTWMEWDRE-(SEQ ID NO：39)、WNNMTWMEWDRE-(SEQ ID NO：40)、IWNNMTWMEWDRE-(SEQ IDNO：And Q IWNNMTWMEWDRE- (SEQ ID NO 41)：42)；
Xb1、Xb2、Xb3、Xb4Separately it is selected from the following amino acid of D types or L-type：Glutamic acid (E), glutamine (Q), day Winter amide (N), serine (S), threonine (T) and tyrosine (Y)；
Xe1、Xe2、Xe3、Xe4Separately it is selected from the following amino acid of D types or L-type：Isoleucine (I), valine (V), Nor-leucine (Nle), leucine (L) and alanine (A)；
Xd3、Xd4Separately it is selected from the following amino acid of D types or L-type：Leucine (L), nor-leucine (Nle), paddy acyl Amine (Q), asparagine (N) and serine (S)；
Xa4Following amino acid selected from D types or L-type：Serine (S), glutamine (Q), asparagine (N)；
B is selected from the lysine (K) or arginine (R) of D types or L-type；
Y2Sequence or small molecule chosen from the followings：-WASLWNWF(SEQ ID NO：43), cholesterol and CH3(CH2)nCOOH, wherein n is the integer of 4-16；Preferably, 6,10,12,14,16 n.
In one embodiment of the invention, the Formulas I polypeptide, its derivative, its stereoisomer or its without life Manage the salt of toxicity, wherein the Formulas I polypeptide compound chosen from the followings：
1.WMEWDRE AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：1)；
2.WMEWDRE IEELAKK SEELAKK IEEQAKK QEESAKK(SEQ ID NO：2)；
3.WMEWDRE IEELIKK SEELAKK IEEQAKK QEESAKK(SEQ ID NO：3)；
4.WMEWDRE IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：4)；
5.WMEWDRE IEELIRR SEELIRR IEEQIRR QEESIRR(SEQ ID NO：5)；
6.WMEWDRE IAELIKK SAELIKK IAEQIKK QAESIKK(SEQ ID NO：6)；
7.WMEWDRE IQELIKK SIELIKK IQEQIKK QIESIKK(SEQ ID NO：7)；
8.WMEWDRE IEELAKK SEELAKK AEELAKK AEELAKK(SEQ ID NO：8)；
9.WMEWDRE IEELAKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：9)；
10.WMEWDRE IEELIKK SEELIKK IEEQAKK QEESIKK(SEQ ID NO：10)；
11.WMEWDRE IEELIKK SEELAKK IEEQIKK QEESIKK(SEQ ID NO：11)；
12.WMEWDRE IEELIKK SEELIKK IEEQIKK QEESAKK(SEQ ID NO：12)；
13.AEELAKK AEELAKK AEELAKK AEELAKK WASLWNWF(SEQ ID NO：13)；
14.IEELAKK AEELAKK AEELAKK AEELAKK WASLWNWF(SEQ ID NO：14)；
15.AEEFAKK AEELAKK AEELAKK AEELAKK WASLWNWF(SEQ ID NO：15)；
16.IEEFAKK AEELAKK AEELAKK AEELAKK WASLWNWF(SEQ ID NO：16)；
17.IEEYAKK AEELAKK AEELAKK AEELAKK WASLWNWF(SEQ ID NO：17)；
18.IEEFAKK QEEVAKK AEELAKK AEELAKK WASLWNWF(SEQ ID NO：18)；
19.IEEFAKK QEELAKK AEELAKK AEELAKK WASLWNWF(SEQ ID NO：19)；
20.IEEFAKK QEELAKK IEELAKK AEELAKK WASLWNWF(SEQ ID NO：20)；
21.IEEFAKK QEELAKK VEELAKK AEELAKK WASLWNWF(SEQ ID NO：21)；
22.IEEFAKK QEEVAKK IEELAKK AEELAKK WASLWNWF(SEQ ID NO：22)；
23.IEEFAKK QEEVAKK IEELAKK IEELAKK WASLWNWF(SEQ ID NO：23)；
24.IEEFAKK SEELAKK AEELAKK AEELAKK WASLWNWF(SEQ ID NO：24)；
25.IEEFAKK SEELAKK IEELAKK AEELAKK WASLWNWF(SEQ ID NO：25)；
26.IEEFAKK SEELAKK VEELAKK AEELAKK WASLWNWF(SEQ ID NO：26)；
27.IEEFMKK QEEVMKK IEELMKK IEELMKK WASLWNWF(SEQ ID NO：27)；
28.IEEFSKK SEELSKK IEELSKK AEELSKK WASLWNWF(SEQ ID NO：28)；
29.ISEFAKK SSELAKK ISELAKK ASELAKK WASLWNWF(SEQ ID NO：29)；
30.WEEFAKK SEELAKK IEELAKK AEELAKK WASLWNWF(SEQ ID NO：30)；
31.YEEFAKK SEELAKK IEELAKK AEELAKK WASLWNWF(SEQ ID NO：31)；
32.Na l-EEFAKK SEELAKK IEELAKK AEELAKK WASLWNWF(SEQ ID NO：32)；
33.IEEFAKK SEELAKK IEELAKK AEELAKK WASLWNWFRGD(SEQ ID NO：33)；And
34.RGDIEEFAKK SEELAKK IEELAKK AEELAKK WASLWNWF(SEQ ID NO：34).
Wherein, SEQ ID NO：1、SEQ ID NO：13、SEQ ID NO：Sequence shown in 15 is negative control sequence.
In one embodiment of the invention, the Formulas I polypeptide, its derivative, its stereoisomer or its without life The salt for managing toxicity, selected from compound 4-9 above, 20,24-26 and 30-34.
Another aspect of the present invention is related to a kind of pharmaceutical composition, and containing at least one above-mentioned Formulas I polypeptide, it spreads out The salt and pharmaceutically acceptable carrier or auxiliary material of biology, its stereoisomer or its physiological-toxicity-free.
The present invention still another aspect be related to a kind of HIV fusion inhibitors, containing at least one above-mentioned Formulas I polypeptide, The salt of its derivative, its stereoisomer or its physiological-toxicity-free.
The present invention still another aspect be related to above-mentioned Formulas I polypeptide, its derivative, its stereoisomer or its without physiology Purposes of the salt of toxicity in preparing HIV fusion inhibitors.
The present invention still another aspect be related to above-mentioned Formulas I polypeptide, its derivative, its stereoisomer or its without physiology Purposes of the salt of toxicity in preparing the drug for treating or preventing HIV infection relevant disease especially AIDS.
The still another aspect of the present invention is related to a kind of side treating or preventing HIV infection relevant disease especially AIDS Method, the method include receiving treatment or a effective amount of Formulas I polypeptide of object prevented, its derivative, its solid to giving The salt of isomers or its physiological-toxicity-free.
In the present invention, term " natural " refers to naturally occurring, without artificial modification, such as HIV-1gp41 itself Amino acid sequence etc..
In the present invention, term " non-natural " refers to artificially designing, and natural different, such as to derived from directly naturally Sequence is engineered, the sequence etc. after modification.
In the present invention, term " hydrophobic amino acid " refers to the amino acid that side chain is hydrophobic group, including：Ala, Val, Leu, Ile, Met, Phe, Trp etc..
In the present invention, term " hydrophilic amino acid " refers to that side chain contains and can act on the hydrophilic radical to form hydrogen bond with water Amino acid, including：Ser, Thr, Cys, Asp, Asn, Glu, Gln, Arg, Lys, His, Tyr etc..
In the present invention, term " acidic amino acid " refers to the carboxylic amino acid of side chain, including：Glu, Asp etc..
In the present invention, term " basic amino acid " refers to amino acid of the side chain containing amino or guanidine radicals, including：Lys, Arg Deng.
In the present invention, term " being acted on adipose membrane " is the hydrophobic group for referring to act on the lipid double sublayer of cell membrane Group or peptide sequence, including：Cholesterol, long chain fatty acids etc..
Specific implementation mode
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is It can be with conventional products that are commercially available.
The abbreviation being used in the present invention has following meaning：
AIDS (Acquired Immure Deficiency Syndrome) AIDS, acquired immunodeficiency syndrome
Ala (Alanine, A) alanine
Arg (Arginine, R) arginine
Asn (Asparagine, N) asparagine
Asp (Asparticacid, D) aspartic acid
DCM (Dichloromethane) dichloromethane
DMF (N, N-Dimethyl malonate) dimethylformamide
Env (Envelope glycoprotein) envelope glycoprotein
ESI-MS (Electronic spray ion mass spectroscopy) electrospray ionization mass spectrum
Fmoc (Fluorenylmethoxycarbonyl) fluorenylmethyloxycarbonyl
Gly (Glycine, G) glycine
Gln (Glutamine, Q) paddy acyl ammonia
Glu (Glutamic acid, E) glutamic acid
6-HB (six-helix bundle) six conveyor screws
- 1,1,3,3- tetramethylurea hexafluorophosphoric acids of HBTU 2- (1H-1- hydroxybenzotriazoles)
His (Histidine, H) histidine
HoBt (1-Hydroxyl benzotriazole anhydrous) 1- hydroxy benzo triazoles
HR1 (N-terminal heptad repeat, NHR) N-terminal repetitive sequence
HR2 (C-terminal heptad repeat, CHR) C-terminal repetitive sequence
HIV (Human Immunodeficiency Virus)) human immunodeficiency virus
HIV-1 human Mn superoxide dismutases
HPLC (High performance liquid chromatography) high performance liquid chromatography
Ile (Isoleucine, I) isoleucine
Leu (Leucine, L) leucine
Met (Methionine, M) methionine
Nal nor-leucines
Lys (Lysine, K) lysine
Phe (Phenylalanine, F) phenylalanine
Ser (Serine, S) serine
TFA (trifluoroacetic acid) trifluoroacetic acid
Thr (Threonie, T) threonine
Trp (Tryptophan, W) tryptophan
Tyr (Tyrosine, Y) tyrosine
Val (Valine, V) valine
Solid-phase synthesized carrier Rink amide resins used in embodiment are that Tianjin Nankai synthesizes responsibility Co., Ltd product； HBTU, HOBT, DIEA and the non-natural amino acid of fmoc-protected natural amino acid or D types be Shanghai gill biochemical corp with And Chengdu Cheng Nuo New Technology Co., Ltd. product.N-Methyl pyrrolidone (NMP) is ACROS Products；Trifluoroacetic acid (TFA) it is Beijing Bo Maijie Science and Technology Ltd.s product；DMF, DCM are Samsung of South Korea product；Trifluoroacetic acid aqueous solution is Fisher Products.Other reagents are such as domestic analysis net product without explanation.
Embodiment 1：The preparation of compound 1
Using the Fmoc solid-phase peptide synthesis of standard.All equal C-terminals of peptide sequence are amidation, and N-terminal is acetylation.Choosing With Rink Amide resins, peptide chain is extended from C-terminal to N-terminal.Condensing agent is HBTU/HOBt/DIEA.Deprotection agent is piperidines/DMF Solution.Decomposition agent is trifluoroacetic acid (TFA), is lyophilized and preserves after thick peptide water dissolution.With medium pressure liquid chromatography method or high pressure liquid phase color Spectrometry (HPLC) is isolated and purified, pure peptide content ＞ 90%.MALDI TOF MS (MALDI-TOF- MS peptide sequence molecular weight) is determined.
Microwave Peptide systhesis condition is as follows：
Amino acid：The DMF solution of 0.2M,
Activator：The DMF solution of 0.45M HBTU/HOBt,
Activate alkali：The nmp solution of 2M DIEA,
Deprotection agent：The DMF solution of 20%v/v piperidines,
Closed reagent：The DMF solution of 20%v/v acetic anhydrides.
It weighs in Rink Amide resins 0.5g (0.25mmol) merging CEM microwave Peptide synthesizer reactors, then will Amino acid, activator activate alkali, and deprotecting regent is more with CEM microwave full-automatics after closed reagent is configured by above-mentioned concentration Peptide synthesizer is synthesized.It is shunk with absolute methanol after peptide resin washs 3 times with DMF after the completion, room temperature in vacuo drying obtains peptide tree Fat 2.05g.
Lysate (percent by volume)：Trifluoroacetic acid: dithioglycol: metacresol: water=82.5: 10: 5: 2.5.
The cracking of peptide resin：The synthetic peptide resin 2.05g of microwave synthesizer is weighed, is put into 250ml eggplant-shape bottles, ice Bath, electromagnetic agitation.The amount that 10ml is added by 1 gram of peptide resin prepares lysate.TFA needs advance ice bath cooling 30min or advance It deposits in refrigerator and uses；Prepared lysate is added in the peptide resin under condition of ice bath, electromagnetic agitation, resin becomes orange Red reacts 30min under condition of ice bath, then, removes ice bath, room temperature is further continued for being stirred to react 90min, and reaction is completed.Acutely stir The lower addition cold ether 200ml into reactor is mixed, white precipitate is precipitated, continues to stir 30min；Funnel filter is filtered with the sand core of G4 Go out precipitate, is washed 3 times, dried repeatedly with cold ether.Distilled water 50ml is added, acetonitrile 5ml makes solid fully dissolve, filters, Thick peptide 1.03g is lyophilized to obtain in filtrate.
The thick peptide of gained is purified with medium-pressure or high pressure chromatography.Chromatographic column is C18 columns, and eluant, eluent is acetonitrile, water and a small amount of Acetic acid.Concrete operation step：Thick peptide 1.00g is weighed, adds water 20ml, acetonitrile 5ml that solid is made to dissolve, centrifugation 10min (3000 turns/ Minute), take supernatant loading.Chromatographic column is balanced with the glacial acetic acid solution of 15% acetonitrile/water/0.1% 200ml in advance.Loading is subsequent It is continuous to be rinsed with the glacial acetic acid solution 200ml of 15% acetonitrile/water/0.1%, efficient liquid phase detection eluent ingredient.It is detected according to liquid phase As a result ethane nitrile content is gradually risen, until purified polypeptide main peak is eluted out.Merge eluent, rotary evaporation removal is big Partial solvent, is lyophilized to obtain pure peptide, and HPLC detection levels are more than 90%.
Pure peptide is through its molecular weight (table 1 seen below) of MALDI-TOF-MS ESI mass spectrum confirmations.
Embodiment 2-34：The preparation of compound 2-34
The compound of number 2- numbers 34 is synthesized by embodiment (1) method, and only corresponding amino acid residue is replaced It changes.The table 1 that the molecular weight of compound 2-34 is seen below.
Embodiment 35：Inhibit the detection of HIV-1 bioactivity
1) cell-cell fusion activity that compound inhibits HIV-1 to mediate evaluates (IC50)
Dye the Cell-Cell Fusion that transfer method detection HIV-1 is mediated：HIV-1IIIBH9 cells (the H9/HIV- of infection 1IIIB) marked by a kind of fluorescent reagent Calcein-AM (Molecular Probes, Inc., Eugene, OR), then in 96 holes It is added or is not added with test-compound and MT-2 cells (ratio=1: 10) co-cultivation 2h for 37 DEG C in plate.Compound is tested from 250 μ g/ Twice of gradient dilution of ml concentration.The reversed fluorescence microscope of cell of fusion and the Calcein label HIV-1 infection that do not merge (Zeiss, Germany) is counted.Calculate IC50Value.
2) ELISA detection compounds inhibit gp41 6-HB to form activity (IC50)
Sandwich ELISA method detection C peptides inhibit gp41 6-HB to form activity：Compound is tested from 250 μ g/ml concentration two Times gradient dilution.N36 peptides (2 μM) are mixed with sample to be tested, in 37 DEG C of preculture 30min, add C34 (2 μM), 37 DEG C of incubations Then 30min is added them into the ELISA Plate (Costar, Corning Inc., Corning, NY) closed, 37 DEG C Incubate 1h；Sequentially add 6-HB monoclonal antibody specific NC-1, the IgG of biotin labeling, SA-HRP, TMB.Detect 450nm Locate the absorbance value of (using 570nm as reference).Calculate IC50Value.
According to the method described above, the table 1 that determination of activity result is seen below.
Table 1：Polypeptide inhibits the cell fusion of HIV mediations and 6-HB to form Activity Results
Table 1 illustrates that compound 1-34 shows the cell fusion and inhibit 6-HB that a degree of inhibition HIV-1 is mediated Form activity.Wherein compound 4,9,12 inhibits the cell fusion activity level and the basic phases of marketed drug T-20 of HIV-1 mediations When, and gp41 nuclear structures 6-HB can be significantly inhibited and formed, show that its mechanism of action may be different from T-20, mainly passes through Inhibit the formation of 6-HB and reaches anti-fusion purpose.
Although the specific implementation mode of the present invention has obtained detailed description, it will be understood to those of skill in the art that.Root According to all introductions having disclosed, those details can be carry out various modifications and be replaced, these change the guarantor in the present invention Within the scope of shield.The full scope of the present invention is given by the appended claims and any equivalents thereof.
<110>Inst of Toxic Medicinal Materials, P.L.A. Academy of Military Medical Sciences
<120>Polypeptide, composition and the purposes of AntiHIV1 RT activity infection
<130>IDC100097
<160>43
<170>PatentIn version 3.2
<210>1
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<212>PRT
<213>Artificial sequence
<400>1
Trp Met Glu Trp Asp Arg Glu Ala Glu Glu Leu Ala Lys Lys Ala Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Ala Glu Glu Leu
20 25 30
Ala Lys Lys
35
<210>2
<211>35
<212>PRT
<213>Artificial sequence
<400>2
Trp Met Glu Trp Asp Arg Glu Ile Glu Glu Leu Ala Lys Lys Ser Glu
1 5 10 15
Glu Leu Ala Lys Lys Ile Glu Glu Gln Ala Lys Lys Gln Glu Glu Ser
20 25 30
Ala Lys Lys
35
<210>3
<211>35
<212>PRT
<213>Artificial sequence
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Trp Met Glu Trp Asp Arg Glu Ile Glu Glu Leu Ile Lys Lys Ser Glu
1 5 10 15
Glu Leu Ala Lys Lys Ile Glu Glu Gln Ala Lys Lys Gln Glu Glu Ser
20 25 30
Ala Lys Lys
35
<210>4
<211>35
<212>PRT
<213>Artificial sequence
<400>4
Trp Met Glu Trp Asp Arg Glu Ile Glu Glu Leu Ile Lys Lys Ser Glu
1 5 10 15
Glu Leu Ile Lys Lys Ile Glu Glu Gln Ile Lys Lys Gln Glu Glu Ser
20 25 30
Ile Lys Lys
35
<210>5
<211>35
<212>PRT
<213>Artificial sequence
<400>5
Trp Met Glu Trp Asp Arg Glu Ile Glu Glu Leu Ile Arg Arg Ser Glu
1 5 10 15
Glu Leu Ile Arg Arg Ile Glu Glu Gln Ile Arg Arg Gln Glu Glu Ser
20 25 30
Ile Arg Arg
35
<210>6
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<213>Artificial sequence
<400>6
Trp Met Glu Trp Asp Arg Glu Ile Ala Glu Leu Ile Lys Lys Ser Ala
1 5 10 15
Glu Leu Ile Lys Lys Ile Ala Glu Gln Ile Lys Lys Gln Ala Glu Ser
20 25 30
Ile Lys Lys
35
<210>7
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<212>PRT
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Trp Met Glu Trp Asp Arg Glu Ile Gln Glu Leu Ile Lys Lys Ser Ile
1 5 10 15
Glu Leu Ile Lys Lys Ile Gln Glu Gln Ile Lys Lys Gln Ile Glu Ser
20 25 30
Ile Lys Lys
35
<210>8
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<212>PRT
<213>Artificial sequence
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Trp Met Glu Trp Asp Arg Glu Ile Glu Glu Leu Ala Lys Lys Ser Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Ala Glu Glu Leu
20 25 30
Ala Lys Lys
35
<210>9
<211>35
<212>PRT
<213>Artificial sequence
<400>9
Trp Met Glu Trp Asp Arg Glu Ile Glu Glu Leu Ala Lys Lys Ser Glu
1 5 10 15
Glu Leu Ile Lys Lys Ile Glu Glu Gln Ile Lys Lys Gln Glu Glu Ser
20 25 30
Ile Lys Lys
35
<210>10
<211>35
<212>PRT
<213>Artificial sequence
<400>10
Trp Met Glu Trp Asp Arg Glu Ile Glu Glu Leu Ile Lys Lys Ser Glu
1 5 10 15
Glu Leu Ile Lys Lys Ile Glu Glu Gln Ala Lys Lys Gln Glu Glu Ser
20 25 30
Ile Lys Lys
35
<210>11
<211>35
<212>PRT
<213>Artificial sequence
<400>11
Trp Met Glu Trp Asp Arg Glu Ile Glu Glu Leu Ile Lys Lys Ser Glu
1 5 10 15
Glu Leu Ala Lys Lys Ile Glu Glu Gln Ile Lys Lys Gln Glu Glu Ser
20 25 30
Ile Lys Lys
35
<210>12
<211>35
<212>PRT
<213>Artificial sequence
<400>12
Trp Met Glu Trp Asp Arg Glu Ile Glu Glu Leu Ile Lys Lys Ser Glu
1 5 10 15
Glu Leu Ile Lys Lys Ile Glu Glu Gln Ile Lys Lys Gln Glu Glu Ser
20 25 30
Ala Lys Lys
35
<210>13
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Ala Glu Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Ala Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
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<212>PRT
<213>Artificial sequence
<400>14
Ile Glu Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Ala Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>15
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Ala Glu Glu Phe Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Ala Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>16
<211>36
<212>PRT
<213>Artificial sequence
<400>16
Ile Glu Glu Phe Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Ala Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>17
<211>36
<212>PRT
<213>Artificial sequence
<400>17
Ile Glu Glu Tyr Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Ala Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>18
<211>36
<212>PRT
<213>Artificial sequence
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Ile Glu Glu Phe Ala Lys Lys Gln Glu Glu Val Ala Lys Lys Ala Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>19
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<212>PRT
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<400>19
Ile Glu Glu Phe Ala Lys Lys Gln Glu Glu Leu Ala Lys Lys Ala Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
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<211>36
<212>PRT
<213>Artificial sequence
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Ile Glu Glu Phe Ala Lys Lys Gln Glu Glu Leu Ala Lys Lys Ile Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
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Ile Glu Glu Phe Ala Lys Lys Gln Glu Glu Leu Ala Lys Lys Val Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>22
<211>36
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<400>22
Ile Glu Glu Phe Ala Lys Lys Gln Glu Glu Val Ala Lys Lys Ile Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
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<211>36
<212>PRT
<213>Artificial sequence
<400>23
Ile Glu Glu Phe Ala Lys Lys Gln Glu Glu Val Ala Lys Lys Ile Glu
1 5 10 15
Glu Leu Ala Lys Lys Ile Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>24
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<212>PRT
<213>Artificial sequence
<400>24
Ile Glu Glu Phe Ala Lys Lys Ser Glu Glu Leu Ala Lys Lys Ala Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>25
<211>36
<212>PRT
<213>Artificial sequence
<400>25
Ile Glu Glu Phe Ala Lys Lys Ser Glu Glu Leu Ala Lys Lys Ile Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>26
<211>36
<212>PRT
<213>Artificial sequence
<400>26
Ile Glu Glu Phe Ala Lys Lys Ser Glu Glu Leu Ala Lys Lys Val Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>27
<211>36
<212>PRT
<213>Artificial sequence
<400>27
Ile Glu Glu Phe Met Lys Lys Gln Glu Glu Val Met Lys Lys Ile Glu
1 5 10 15
Glu Leu Met Lys Lys Ile Glu Glu Leu Met Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>28
<211>36
<212>PRT
<213>Artificial sequence
<400>28
Ile Glu Glu Phe Ser Lys Lys Ser Glu Glu Leu Ser Lys Lys Ile Glu
1 5 10 15
Glu Leu Ser Lys Lys Ala Glu Glu Leu Ser Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>29
<211>36
<212>PRT
<213>Artificial sequence
<400>29
Ile Ser Glu Phe Ala Lys Lys Ser Ser Glu Leu Ala Lys Lys Ile Ser
1 5 10 15
Glu Leu Ala Lys Lys Ala Ser Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>30
<211>36
<212>PRT
<213>Artificial sequence
<400>30
Trp Glu Glu Phe Ala Lys Lys Ser Glu Glu Leu Ala Lys Lys Ile Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>31
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<212>PRT
<213>Artificial sequence
<400>31
Tyr Glu Glu Phe Ala Lys Lys Ser Glu Glu Leu Ala Lys Lys Ile Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>32
<211>36
<212>PRT
<213>Artificial sequence
<400>32
Nal Glu Glu Phe Ala Lys Lys Ser Glu Glu Leu Ala Lys Lys Ile Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe
35
<210>33
<211>39
<212>PRT
<213>Artificial sequence
<400>33
Ile Glu Glu Phe Ala Lys Lys Ser Glu Glu Leu Ala Lys Lys Ile Glu
1 5 10 15
Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp Ala Ser Leu
20 25 30
Trp Asn Trp Phe Arg Gly Asp
35
<210>34
<211>39
<212>PRT
<213>Artificial sequence
<400>34
Arg Gly Asp Ile Glu Glu Phe Ala Lys Lys Ser Glu Glu Leu Ala Lys
1 5 10 15
LysIle Glu Glu Leu Ala Lys Lys Ala Glu Glu Leu Ala Lys Lys Trp
20 25 30
Ala Ser Leu Trp Asn Trp Phe
35
<210>35
<211>7
<212>PRT
<213>Artificial sequence
<400>35
Trp Met Glu Trp Asp Arg Glu
1 5
<210>36
<211>8
<212>PRT
<213>Artificial sequence
<400>36
Thr Trp Met Glu Trp Asp Arg Glu
1 5
<210>37
<211>9
<212>PRT
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Met Thr Trp Met Glu Trp Asp Arg Glu
1 5
<210>38
<211>10
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Asn Met Thr Trp Met Glu Trp Asp Arg Glu
1 5 10
<210>39
<211>11
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<400>39
Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu
1 5 10
<210>40
<211>12
<212>PRT
<213>Artificial sequence
<400>40
Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu
1 5 10
<210>41
<211>13
<212>PRT
<213>Artificial sequence
<400>41
Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu
1 5 10
<210>42
<211>14
<212>PRT
<213>Artificial sequence
<400>42
Gln Ile Trp Asn Asn Met Thr Trp Met Glu Trp Asp Arg Glu
1 5 10
<210>43
<211>8
<212>PRT
<213>Artificial sequence
<400>43
Trp Ala Ser Leu Trp Asn Trp Phe
1 5

Claims (8)

1. the salt of polypeptide or its physiological-toxicity-free shown in Formulas I,
Y1-IXb1ELXe1BB-SXb2ELXe2BB-IXb3EXd3Xe3BB-Xa4Xb4EXd4Xe4BB-Y2Formulas I
Wherein,
Y1For WMEWDRE- or Y1Missing；
Xb1、Xb2、Xb3Separately it is selected from glutamic acid, glutamine and serine；
Xb4Selected from glutamic acid, serine, alanine and isoleucine；
Xe1、Xe2、Xe3、Xe4Separately it is selected from isoleucine and alanine；
Xd3Selected from leucine and glutamine；
Xd4Selected from leucine and serine；
Xa4For glutamine；
B is lysine or arginine；
Y2For-WASLWNWF or Y2Missing.
2. the salt of a kind of polypeptide or its physiological-toxicity-free, wherein the polypeptide is selected from SEQ ID NO：2-12、SEQ ID NO：14 With SEQ ID NO：At least one of the polypeptide of sequence shown in 16-34.
3. a kind of pharmaceutical composition, containing described in any one of at least one claim 1-2 polypeptide or its without physiology poison The salt and pharmaceutically acceptable carrier of property.
4. a kind of pharmaceutical composition, containing described in any one of at least one claim 1-2 polypeptide or its without physiology poison The salt and pharmaceutically acceptable auxiliary material of property.
5. a kind of HIV fusion inhibitors, containing described in any one of at least one claim 1-2 polypeptide or its without physiology The salt of toxicity.
6. the salt of the polypeptide or its physiological-toxicity-free described in any one of claim 1-2 is in preparing HIV fusion inhibitors Purposes.
7. the salt of the polypeptide or its physiological-toxicity-free described in any one of claim 1-2 is being prepared for treating or preventing HIV Infect the purposes in the drug of relevant disease.
8. purposes according to claim 7, wherein the HIV infection relevant disease is AIDS.
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