CN103122025B - Suppress the micromolecule polypeptide conjugate of HIV - Google Patents
Suppress the micromolecule polypeptide conjugate of HIV Download PDFInfo
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- CN103122025B CN103122025B CN201110368739.4A CN201110368739A CN103122025B CN 103122025 B CN103122025 B CN 103122025B CN 201110368739 A CN201110368739 A CN 201110368739A CN 103122025 B CN103122025 B CN 103122025B
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- ieelikk
- βala
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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
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Abstract
The invention belongs to biomedicine field, it is related to a kind of micromolecule polypeptide conjugate of AntiHIV1 RT activity infection, in particular it relates to Formulas I Sm‑L1‑Xa1EEXd1Xe1KK Xa2EE Xd2Xe2KK Xa3EEXd3Xe3KK Xa4EEXb4Xe4KK‑L2The salt of micromolecule polypeptide conjugate, its derivative, its stereoisomer or its physiological-toxicity-free shown in Chol Formulas I.The invention further relates to the pharmaceutical composition of the salt containing above-mentioned Formulas I micromolecule polypeptide conjugate, its derivative, its stereoisomer or its physiological-toxicity-free, and Formulas I micromolecule polypeptide conjugate, its derivative, the purposes of salt relevant disease especially acquired immunodeficiency syndrome (AIDS) caused by HIV is treated or prevented of its stereoisomer or its physiological-toxicity-free.
Description
Technical field
The invention belongs to biomedicine field, it is related to a kind of small molecule and polypeptide conjugate for suppressing HIV, specifically
Ground, is related to the salt of conjugate shown in Formulas I, its derivative, its stereoisomer or its physiological-toxicity-free.The invention further relates to
The pharmaceutical composition of salt containing above-mentioned Formulas I conjugate, its derivative, its stereoisomer or its physiological-toxicity-free, and
Formulas I conjugate, its derivative, its stereoisomer or its physiological-toxicity-free salt it is related caused by HIV is treated or prevented
The purposes of disease especially acquired immunodeficiency syndrome (AIDS, i.e. AIDS).
Sm-L1-Xa1EEXd1Xe1KK Xa2EE Xd2Xe2KK Xa3EEXd3Xe3KK Xa4EEXb4Xe4KK-L2- Chol Formulas I.
Background technology
Lethal sexually transmitted disease caused by AIDS infects mainly due to human Mn superoxide dismutase (HIV-1), complete
Ball scope is popular.The anti-HIV-1 medicines clinically applied at present, are aided with highly active antiretroviral therapy, can be in certain journey
Extend the life span of HIV person on degree and improve its quality of life.But, because HIV vaccine progress is slow and
Drug resistance problems are increasingly apparent, and it is still the task of top priority to research and develop new inverase.HIV fusion inhibitors (HIV fusion
Inhibitors) it is new inverase of the viral interference into target cell, it is in the viral biography of the initial link cut-out of infection
Broadcast, this is for preventing and controlling HIV-1 infection to acquire a special sense, thus the focus studied as new mechanism inverase.
Gp41 is the specific proteins for mediating HIV-1 and target cell membrane fusion, is the action target of fusion inhibitor.Gp41
Extracellular region exist two merged with film closely related helical structure functional areas, i.e. N-terminal repetitive sequence (HR1) and C end
Hold repetitive sequence (HR2).In film fusion process, HR2 and HR1 interacts, and forms a six conveyor screw core texture (6-
HB).T20 is that the fusion of 36 amino acid residues of having derived from gp41HR2 regions suppresses polypeptide, in 2003 through the U.S.
FDA approval listings, are the HIV-1 fusion inhibitors of currently the only listing.T20 can the emulative spiral trimerization constituted with HR1
Body is combined, and occupies HR2 action site, and then suppress 6-HB formation so that film fusion process can not be completed.
T20 listing opens the frontier that polypeptide drug controls HIV-1.But, T20 has some defects in itself
And deficiency.It is drug resistance problems first：Because T20 is derived from natural HR2 sequences completely, target mutation is had a low resistance, held
It is also easy to produce drug resistance.36-45 residues (GIVQQQNNLL) of HR1 are the main portions that T20 is combined, and the mutation of single residue is led
T20 susceptibilitys are caused to decline 5-10 times, two residue mutations can then cause susceptibility to decline 100 times.Secondly, stability in T20 bodies
Difference, is easily easily degraded by proteases, and bioavilability is low.How solving drug resistance and improving enzymolysis stability is new HIV-1 fusions
The Main way of inhibitor research.
Based on above mentioned problem, resolution policy main at present is the target binding site for avoiding T20, introduces and is different from T20
New functional sequence overcome drug resistance；Meanwhile, spiralization and stable factor are added, the helicity and stably of sequence is improved
Property, improve enzymolysis stability and inhibitory activity.Such as second generation polypeptide fusion inhibitor T-1249, added and N- in its N-terminal
Trimer hydrophobic pockets binding sequence (WQEWEQKI), makes its activity improve an order of magnitude than T20；And for example the third generation melts
Conjunction inhibitor T-1144, and T20 target action site are entirely different, predominantly HR1 hydrophobic pocket area (WEAWERAI).
I phase clinical study results show that T-1144 can significantly inhibit T20 Drug resistance strains, while showing higher activity than T20
And more preferable pharmacokinetic property.In addition, 5HR series polypeptides have started the three-dimensional based on target gp41HR1 spiral tripolymers
The new approaches of the complete non-natural alpha helical peptides of crystal structure appliance computer Computer Aided Design.Using 5HR as guide structure, draw in its N-terminal
Inlet pocket land (WMEWDRE), C-terminal introduces adipose membrane land (WASLWNWF) so that suppresses fusion-activity and has obtained significantly
Improve.
The hydrophobic pocket on Gp41 N-trimer surfaces is the action target spot of small molecule fusion inhibitor simultaneously.Such as NB-2,
Its EC50Value reaches 1.04 μM；A12It is same to show suppression HIV replication activities, EC in micromolar levels50It is worth for 0.69 μM；From olive
The natural small molecule compounds hydroxytyrosol (hydroxytyrosol, HT) extracted in olive leaf suppresses HIV replication activities and reaches 50 μ
M.But, small molecule fusion inhibitor activity is far away from peptides fusion inhibitor.Its reason is：(1) single small molecule
It is that part occupies hydrophobic pocket, it is low with target adhesion, it is not enough to Reverse transcriptase 6-HB and is formed；(2) single small molecule
Recognition capability is not strong, and the local concentration near target spot is not high.
In summary, small molecule is combined by the present inventor with peptides fusion inhibitor, with small molecule substitution peptides fusion
Functional areas PBD and LBD in inhibitor, peptides pharmacophore is conjugated with non-peptides pharmacophore, both is played synergy, if
Brand new HIV fusion inhibitors are counted, the new approaches for suppressing drug resistance are explored.Present invention is completed therefrom.
Conjugate is infected the present invention seeks to the new AntiHIV1 RT activity for designing complete Non-native sequences, T20 drug resistances can be suppressed
HIV strains.
The content of the invention
One aspect of the present invention be related to polypeptide-small molecule conjugates shown in Formulas I, its derivative, its stereoisomer,
Or the salt of its physiological-toxicity-free,
Sm-L1-Xa1EEXd1Xe1KK Xa2EE Xd2Xe2KK Xa3EEXd3Xe3KK Xa4EEXb4Xe4KK-L2- Chol Formulas I
Wherein,
SmFor the small molecule chemical combination that can be specifically bound with HIV-1 gp41 N-trimer surface hydrophobics pocket region
Thing, or SmMissing；
L1For what is enabled small molecule to keep space flexibility and combined with target, the connection between connection peptide and small molecule
Arm, or L1Missing；
Xa1、Xa2、Xa3、Xa4For the natural or Unnatural amino acid residues of a in non-natural HR sequence peptides, Xa1、Xa2、Xa3、
Xa4Can be with identical or different；
EE-KK is the residue combinations to form stable α-helixstructure, respectively positioned at the b of HR sequences, c, f, g, their positions
In the lateral surface of spiral, contacted with solvent, be not involved in the interaction with target residue, mainly use its side chain different electrically
Between form salt bridge effect and formed and stablize α-helixstructure, wherein, E is L-type or D type glutamic acid, and K is the bad ammonia of L-type or D types
Acid.
Xd1、Xd2、Xd3、Xd4For the natural or Unnatural amino acid residues of d in non-natural HR sequence peptides, Xd1、Xd2、Xd3、
Xd4Can be with identical or different；
Xe1、Xe2、Xe3、Xe4For the natural or Unnatural amino acid residues of e in non-natural HR sequence peptides, Xe1、Xe2、Xe3、
Xe4Can be with identical or different；
L2For the linking arm between connecting peptides and cholesterol molecule；
Chol is cholesterol.
Term used herein " stereoisomer " refers to D- the or L- spatial configurations of Formulas I polypeptide.
In one embodiment of the invention, SmSelected from following micromolecular compound：
Wherein, NB2- L is in NB2The pyrrole ring 3 of molecule introduces a carboxyl and is used as the Linker being connected with polypeptide；
mNB2It is that carboxymethyl is introduced on the phenolic hydroxyl group of NB-2 molecules as Linker, it is connected with polypeptide；A12- L is in A12Molecule
Carboxymethyl is introduced at phenolic hydroxyl group as Linker, to be connected with polypeptide.
L1Can be：Natural or alpha-non-natural amino acid；Diacid；Diamines；Glycol；One end is amino, and one end is the poly- of carboxyl
Ethylene glycol；Specifically, L1Can be：
The glycine (Gly) of L-type or D types, alanine (Ala), leucine (Leu), isoleucine (Ile), glutamic acid
(Glu), glutamine (Gln), aspartic acid (Asp), asparagine (Asn), valine (Val), lysine (Lys), serine
(Ser), threonine (Thr), arginine (Arg), histidine (His), tryptophan (Trp), phenylalanine (Phe), tyrosine
(Tyr), cysteine (Cys), methionine (Met).
Beta-alanine (β Ala)；
γ-aminobutyric acid (GABA)
6-aminocaprolc acid (Aca)；
Ethanedioic acid, malonic acid, succinic acid, glutaric acid, adipic acid
Ethylenediamine, propane diamine, butanediamine, pentanediamine, hexamethylene diamine
Ethylene glycol, propane diols, butanediol, pentanediol, hexylene glycol
NH2-CH2CH2-O-CH2CH2-COOH(PEG1)
NH2-CH2CH2-O-CH2CH2-O-CH2CH2-COOH(PEG2)
NH2-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-COOH(PEG3)
Xa1、Xa2、Xa3、Xa4Can be with identical or different, the amino acid selected from following D types or L-type：Glycine (Gly), the third ammonia
Sour (Ala), leucine (Leu), isoleucine (Ile), glutamic acid (Glu), glutamine (Gln), aspartic acid (Asp), asparagus fern
Acid amides (Asn), valine (Val), lysine (Lys), serine (Ser), threonine (Thr), arginine (Arg), histidine
(His), tryptophan (Trp), phenylalanine (Phe), tyrosine (Tyr), cysteine (Cys), methionine (Met).
Xd1、Xd2、Xd3、Xd4Can be with identical or different, the amino acid selected from following D types or L-type：
Glycine (Gly), alanine (Ala), leucine (Leu), isoleucine (Ile), glutamic acid (Glu), glutamine
(Gln), aspartic acid (Asp), asparagine (Asn), valine (Val), lysine (Lys), serine (Ser), threonine
(Thr), arginine (Arg), histidine (His), tryptophan (Trp), phenylalanine (Phe), tyrosine (Tyr), cysteine
(Cys), methionine (Met).
Xe1、Xe2、Xe3、Xe4Can be with identical or different, the amino acid selected from following D types or L-type：Glycine (Gly), the third ammonia
Sour (Ala), leucine (Leu), isoleucine (Ile), glutamic acid (Glu), glutamine (Gln), aspartic acid (Asp), asparagus fern
Acid amides (Asn), valine (Val), lysine (Lys), serine (Ser), threonine (Thr), arginine (Arg), histidine
(His), tryptophan (Trp), phenylalanine (Phe), tyrosine (Tyr), cysteine (Cys), methionine (Met).
L2Can be：
The glycine (Gly) of L-type or D types, alanine (Ala), leucine (Leu), isoleucine (Ile), glutamic acid
(Glu), glutamine (Gln), aspartic acid (Asp), asparagine (Asn), valine (Val), lysine (Lys), serine
(Ser), threonine (Thr), arginine (Arg), histidine (His), tryptophan (Trp), phenylalanine (Phe), tyrosine
(Tyr), cysteine (Cys), methionine (Met).
Monoxone
Bromoacetic acid
Beta-alanine (β Ala)；
γ-aminobutyric acid (GABA)
6-aminocaprolc acid (Aca)；
Ethanedioic acid, malonic acid, succinic acid, glutaric acid, adipic acid
Ethylenediamine, propane diamine, butanediamine, pentanediamine, hexamethylene diamine
Ethylene glycol, propane diols, butanediol, pentanediol, hexylene glycol
NH2-CH2CH2-O-CH2CH2-COOH(PEG1)
NH2-CH2CH2-O-CH2CH2-O-CH2CH2-COOH(PEG2)
NH2-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-COOH(PEG3)
Chol is cholesterol.
In one embodiment of the invention, described Formulas I polypeptide, its derivative, its stereoisomer or its without life
The salt of toxicity is managed, wherein, the Formulas I polypeptide is selected from following compound：
1 HT-------AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：1)；
2 HT-βAla-AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：2)；
3 HT--Aca--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：3)；
4 HT-2Aca--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：4)；
5 HT--PEG1--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：5)；
6 HT--PEG2--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：6)；
7 HT--PEG3--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：7)；
8 AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：8)；
9 HT----------AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
9)；
10 HT-βAla-AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：10)；
11 HT--Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
11)；
12 HT-2Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
12)；
13 HT--PEG1--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
13)；
14 HT--PEG2--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
14)；
15 HT--PEG3--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
15)；
16 HT-------IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：16)；
17 HT-βAla-IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：17)；
18 HT--Aca--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：18)；
19 HT-2Aca--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：19)；
20 HT--PEG1--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：20)；
21 HT--PEG2--IEELAKKIEELAKK IEELAKK IEELAKK(SEQ ID NO：21)；
22 HT--PEG3--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：22)；
23 IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：23)；
24 HT----------IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
24)；
25 HT-βAla-IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：25)；
26 HT--Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
26)；
27 HT-2Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
27)；
28 HT--PEG1--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
28)；
29 HT--PEG2--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
29)；
30 HT--PEG3--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
30)；
31 HT-------IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：31)；
32 HT-βAla-IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：32)；
33 HT--Aca--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：33)；
34 HT-2Aca--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：34)；
35 HT--PEG1--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：35)；
36 HT--PEG2--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：36)；
37 HT--PEG3--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：37)；
38 IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：38)；
39 HT----------IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
39)；
40 HT-βAla-IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：40)；
41 HT--Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
41)；
42 HT-2Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
42)；
43 HT--PEG1--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
43)；
44 HT--PEG2--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
44)；
45 HT--PEG3--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
45)；
46 NB2-------AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：46)；
47 NB2-βAla-AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：47)；
48 NB2--Aca--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：48)；
49 NB2-2Aca--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：49)；
50 NB2--PEG1--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：50)；
51 NB2--PEG2--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：51)；
52 NB2--PEG3--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：52)；
53 NB2----------AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ IDNO：
53)；
54 NB2-βAla-AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
54)；
55 NB2--Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
55)；
56 NB2-2Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
56)；
57 NB2--PEG1--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
57)；
58 NB2--PEG2--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
58)；
59 NB2--PEG3--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
59)；
60 NB2-------IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：60)；
61 NB2-βAla-IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：61)；
62 NB2--Aca--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：62)；
63 NB2-2Aca--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：63)；
64 NB2--PEG1--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：64)；
65 NB2--PEG2--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：65)；
66 NB2--PEG3--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：66)；
67 NB2----------IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ IDNO：
67)；
68 NB2-βAla-IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
68)；
69 NB2--Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
69)；
70 NB2-2Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
70)；
71 NB2--PEG1--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
71)；
72 NB2--PEG2--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
72)；
73 NB2--PEG3--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
73)；
74 NB2-------IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：74)；
75 NB2-βAla-IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：75)；
76 NB2--Aca--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：76)；
77 NB2-2Aca--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：77)；
78 NB2--PEG1--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：78)；
79 NB2--PEG2--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：79)；
80 NB2--PEG3--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：80)；
81 NB2----------IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ IDNO：
81)；
82 NB2-βAla-IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
82)；
83 NB2--Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
83)；
84 NB2-2Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
84)；
85 NB2--PEG1--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
85)；
86 NB2--PEG2--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
86)；
87 NB2--PEG3--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
87)；
88 A12-------AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：88)；
89 A12-βAla-AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：89)；
90 A12--Aca--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：90)；
91 A12-2Aca--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：91)；
92 A12--PEG1--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：92)；
93 A12--PEG2--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：93)；
94 A12--PEG3--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：94)；
95 A12----------AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
95)；
96 A12-βAla-AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：96)；
97 A12--Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
97)；
98 A12-2Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
98)；
99 A12--PEG1--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
99)；
100 A12--PEG2--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
100)；
101 A12--PEG3--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
101)；
102 A12-------IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：102)；
103 A12-βAla-IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：103)；
104 A12--Aca--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：104)；
105 A12-2Aca--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：105)；
106 A12--PEG1--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：106)；
107 A12--PEG2--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：107)；
108 A12--PEG3--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：108)；
109 A12----------IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID
NO：109)；
110 A12-βAla-IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
110)；
111 A12--Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
111)；
112 A12-2Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
112)；
113 A12--PEG1--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
113)；
114 A12--PEG2--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
114)；
115 A12--PEG3--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
115)；
116 A12-------IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：116)；
117 A12-βAla-IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：117)；
118 A12--Aca--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：118)；
119 A12-2Aca--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：119)；
120 A12--PEG1--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：120)；
121 A12--PEG2--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：121)；
122 A12--PEG3--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：122)；
123 A12----------IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID
NO：123)；
124 A12-βAla-IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
124)；
125 A12--Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
125)；
126 A12-2Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
126)；
127 A12--PEG1--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
127)；
128 A12--PEG2--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
128)；
129 A12--PEG3--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
129)；
130 mNB2-------AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：130)；
131 mNB2-βAla-AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：131)；
132 mNB2--Aca--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：132)；
133 mNB2-2Aca--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：133)；
134 mNB2--PEG1--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：134)；
135 mNB2--PEG2--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：135)；
136 mNB2--PEG3--AEELAKK AEELAKK AEELAKK AEELAKK(SEQ ID NO：136)；
137 mNB2----------AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ
IDNO：137)；
138 mNB2-βAla-AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
138)；
139 mNB2--Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
139)；
140 mNB2-2Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
140)；
141 mNB2--PEG1--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
141)；
142 mNB2--PEG2--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
142)；
143 mNB2--PEG3--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol(SEQ ID NO：
143)；
144 mNB2-------IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：144)；
145 mNB2-βAla-IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：145)；
146 mNB2--Aca--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：146)；
147 mNB2-2Aca--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：147)；
148 mNB2--PEG1--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：148)；
149 mNB2--PEG2--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：149)；
150 mNB2--PEG3--IEELAKK IEELAKK IEELAKK IEELAKK(SEQ ID NO：150)；
151 mNB2----------IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ
IDNO：151)；
152 mNB2-βAla-IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
152)；
153 mNB2--Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
153)；
154 mNB2-2Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
154)；
155 mNB2--PEG1--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
155)；
156 mNB2--PEG2--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID NO：
156)；
157 mNB2--PEG3--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol(SEQ ID
NO：157)；
158 mNB2-------IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：158)；
159 mNB2-βAla-IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：159)；
160 mNB2--Aca--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：160)；
161 mNB2-2Aca--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：161)；
162 mNB2--PEG1--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：162)；
163 mNB2--PEG2--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：163)；
164 mNB2--PEG3--IEELIKK IEELIKK IEELIKK IEELIKK(SEQ ID NO：164)；
165 mNB2----------IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ
IDNO：165)；
166 mNB2-βAla-IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
166)；
167 mNB2--Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
167)；
168 mNB2-2Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
168)；
169 mNB2--PEG1--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
169)；
170 mNB2--PEG2--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
170)；
171 mNB2--PEG3--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol(SEQ ID NO：
171)；
172 HT-------IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：172)；
173 HT-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：173)；
174 HT--Aca--IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：174)；
175 HT--2Aca-IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：175)；
176 HT--PEG2--IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：176)；
177 HT--PEG3--IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：177)；
178 NB2-------IEELIKK SEELIKK IEEQIKK QEESIKK(SEQID NO：178)
179 NB2-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：179)；
180 NB2--Aca--IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：180)；
181 NB2-2Aca--IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：181)；
182 NB2--PEG2--IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：182)；
183 NB2--PEG3--IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：183)；
184 A12--βAla--IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：184)；
185 A12---Aca---IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：185)；
186 A12---PEG2---IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：186)；
187 mNB2--βAla--IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：187)；
188 mNB2---Aca---IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：188)；
189 mNB2---PEG2---IEELIKK SEELIKK IEEQIKK QEESIKK(SEQ ID NO：189)；
190 A12----------IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
190)；
191 A12-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
191)；
192 A12--Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
192)；
193 A12-2Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
193)；
194 A12--PEG1--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQID NO：
194)；
195 A12--PEG2--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
195)；
196 A12--PEG3--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
196)；
197 HT----------IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
197)；
198 HT-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
198)；
199 HT--Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
199)；
200 HT-2Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
200)；
201 HT--PEG1--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQID NO：
201)；
202 HT--PEG2--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
202)；
203 HT--PEG3--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
203)；
204 NB2----------IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ
IDNO：204)；
205 NB2-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
205)；
206 NB2--Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
206)；
207 NB2-2Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
207)；
208 NB2--PEG1--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
208)；
209 NB2--PEG2--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
209)；
210 NB2--PEG3--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
210)；
211 HT8----------IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ
IDNO：211)；
212 HT8-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
212)；
213 HT8--Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
213)；
214 HT8-2Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
214)；
215 HT8--PEG1--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
215)；
216 HT8--PEG2--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
216)；
217 HT8--PEG3--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
217)；
218 mNB2----------IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ
IDNO：218)；
219 mNB2-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
219)；
220 mNB2--Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
220)；
221 mNB2-2Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ ID NO：
221)；
222 mNB2--PEG1--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
222)；
223 mNB2--PEG2--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol(SEQ IDNO：
223)；
224 mNB2--PEG3--IEELIKK SEELIKK IEEQIKK QEESIKK-Ala-C-Chol(SEQ IDNO：
224)；
In one embodiment of the invention, described Formulas I polypeptide, its derivative, its stereoisomer or its without life
Manage toxicity salt, its be selected from compound 15-21 above, 36-42,57-63,72-77,85-91,99-105,113-119,
128-133,141-147,168-195 and 197-224.
Another aspect of the present invention is related to a kind of pharmaceutical composition, and it contains at least one above-mentioned Formulas I polypeptide, it spreads out
The salt of biological, its stereoisomer or its physiological-toxicity-free, and pharmaceutically acceptable carrier or auxiliary material.
The present invention still another aspect be related to a kind of HIV fusion inhibitors, its contain 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 HIV fusion inhibitors are prepared.
The present invention still another aspect be related to above-mentioned Formulas I polypeptide, its derivative, its stereoisomer or its without physiology
The salt of toxicity is preparing the purposes in being used to treat or prevent the medicine of HIV relevant disease especially AIDS.
The still another aspect of the present invention is related to a kind of side for treating or preventing HIV relevant disease especially AIDS
Method, described method includes the Formulas I polypeptide, its derivative, its solid to giving the object effective dose for receiving treatment or prevention
The salt of isomers or its physiological-toxicity-free.
Embodiment
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 unreceipted specific in embodiment
Condition person, the condition advised according to normal condition or manufacturer is carried out.Agents useful for same or the unreceipted production firm person of instrument, be
Can be by the conventional products of acquisition purchased in market.
The abbreviation used in the present invention has following implication：
Solid-phase synthesized carrier Rink amide resins used in embodiment are Tianjin Nankai synthesis responsibility Co., Ltd product；
HBTU, HOBT, DIEA and Fmoc protection natural amino acid or D types alpha-non-natural amino acid for Shanghai gill biochemical corp with
And Chengdu Cheng Nuo New Technology Co., Ltd. product.1-METHYLPYRROLIDONE (NMP) is ACROS Products；Trifluoroacetic acid
(TFA) it is Beijing Bo Maijie Science and Technology Ltd.s product；DOPAC, 4-ASA, 5-aminosalicylic acid,
2,5- acetyl butyryls, the tert-butyl alcohol and bromoethyl acetate are ALFA Products；DMF, DCM are Samsung of South Korea product；Color
Pure acetonitrile is composed for Fisher Products.Other reagents are domestic analysis net product such as without explanation.
Embodiment 1：The preparation of compound 1
1.1HT preparation and its connection with linking arm
The synthesis of intermediate 2：
Nitrogen protection is lower with 18.5ml methanol dissolving 0.2g (1.19mmol) compound 1, instills dense H2SO43 drops, lucifuge is returned
Stream 2 hours.Reaction is evaporated reaction solution after terminating, and is dissolved again with ethyl acetate, and use saturation NaHCO3Wash three times.Aqueous phase is closed
And, merging ester phase after three times is extracted with ethyl acetate, neutrality is washed till with saturation NaCl solution.Ester mutually uses anhydrous Na2SO4It is dried
Night, solvent evaporated obtains intermediate 2.Yield 96%.
The synthesis of intermediate 3：
0.21g (1.19mmol) intermediate 2 is dissolved in 15ml anhydrous chloroforms under nitrogen protection, 2,2- dimethoxys are added
Propane (DMP) 1.6ml, camphorsulfonic acid 0.06g (0.24mmol).Lucifuge flows back 4 hours, TLC monitoring reaction (petroleum ethers: ether
=7: 1) reaction uses saturation NaHCO after terminating3Wash three times, chloroform mutually uses anhydrous Na2SO4It is dried overnight, solvent evaporated, which is obtained, slightly produces
Thing.Column chromatographic isolation and purification (petroleum ether: ether=80: 1) obtains intermediate 3, yield 71%.
The synthesis of intermediate 4：
2.54g (11.43mmol) intermediate 3 is dissolved in 100ml anhydrous tetrahydro furans under nitrogen protection, LiAlH is added4
0.22g (5.72mmol), lucifuge is reacted 6 hours.Reaction is added after terminating with water-moistened ether 5ml, rear to add water 0.5ml,
There is precipitation to generate.Filter out solution anhydrous Na after precipitation2SO4It is dried overnight, solvent evaporated obtains crude product.Column chromatographic isolation and purification
(petroleum ether: ether=15: intermediate 4 1), yield 70%.
The synthesis of compound 5：
0.2g (1.03mmol) intermediate 4 is dissolved in 5ml dichloromethane, triethylamine 0.3ml, DMAP 0.01g is added,
Ice bath is stirred.Weigh succinic anhydride 0.24g (2.4mmol) 3ml dichloromethane to dissolve, in suspension, oil bath backflow.10 minutes
The dichloromethane solution of intermediate 4 is instilled with constant pressure funnel afterwards, reaction in 10 minutes is complete after dripping off.It is water-soluble with 10% citric acid
Liquid washes organic phase 1 time, after be washed till neutrality with saturation NaCl solution, use anhydrous Na2SO4It is dried overnight.Solvent evaporated obtains crude product.
Column chromatographic isolation and purification (petroleum ether: ethyl acetate=8: 1) obtains compound 5, yield 80%.
1.2HT and peptide conjugate (compound 1) preparation
Peptide systhesis uses the Fmoc solid phase methods of standard.From 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), and thick peptide is water-soluble
Freeze and preserve after solution.Isolated and purified with medium pressure liquid chromatography method or high pressure lipuid chromatography (HPLC) (HPLC), pure peptide content ＞
90%.MALDI TOF MS (MALDI-TOF-MS) determines peptide sequence molecular weight.
Peptide sequence is synthesized using CEM microwaves Peptide synthesizer, micromolecular compound can be used as last residue and polypeptide N
Amino End Group is condensed, and hydroxyl protecting group is then sloughed under the conditions of polypeptide cleavage, small molecule-polypeptide conjugate is finally obtained.
Synthesis condition is as follows：
Protected amino acid or micromolecular compound：0.2M DMF solution,
Activator：0.45M HBTU/HOBt DMF solution,
Activate alkali：2M DIEA nmp solution,
Deprotection agent：The DMF solution of 20%v/v piperidines,
Closed reagent：The DMF solution of 20%v/v acetic anhydrides.
Weigh Rink Amide resins 0.5g (0.25mmol) to insert in CEM microwave Peptide synthesizer reactors, then will
Amino acid, small molecule, activator activates alkali, and deprotecting regent is complete with CEM microwaves after closed reagent is configured by above-mentioned concentration
Automatic Peptide synthesizer is synthesized.After the completion of peptide resin washed after 3 times and to be shunk with absolute methanol with DMF, room temperature in vacuo is dried,
Obtain peptide resin 2.05g.
Lysate (percent by volume)：Trifluoroacetic acid: dithioglycol: metacresol: water=82.5: 10: 5: 2.5.
The cracking of peptide resin (connection small molecule HT)：The synthetic peptide resin 2.05g of microwave synthesizer is weighed, is put into
In 250ml eggplant-shape bottles, ice bath, electromagnetic agitation.The amount for adding 10ml by 1 gram of peptide resin prepares lysate.TFA needs advance ice bath drop
Warm 30min or advance deposit in refrigerator use；The lysate prepared is added in the peptide resin under condition of ice bath, electricity
Magnetic is stirred, and resin becomes orange red, and 30min is reacted under condition of ice bath, then, ice bath is removed, room temperature is further continued for stirring reaction 90min,
Reaction is completed.The lower addition cold diethyl ether 200ml into reactor is stirred vigorously, white precipitate is separated out, continues to stir 30min；Use G4
Core filter funnel and filter out precipitate, with cold diethyl ether cyclic washing 3 times, dry.Distilled water 50ml is added, acetonitrile 5ml makes solid
Body fully dissolves, and filters, and filtrate is lyophilized that N-terminal connects the thick peptide 1.03g of small molecule.
The thick peptide of gained connection small molecule is purified with medium-pressure or high pressure chromatogram.Chromatographic column is C18 posts, and eluant, eluent is second
Nitrile, water and a small amount of acetic acid.Concrete operation step：Thick peptide 1.00g is weighed, add water 20ml, acetonitrile 5ml makes solid dissolving, centrifuged
10min (3000 revs/min), takes supernatant loading.Chromatographic column is in advance with the glacial acetic acid solution 200ml of 15% acetonitrile/water/0.1%
Balance.Continue to be rinsed with the glacial acetic acid solution 200ml of 15% acetonitrile/water/0.1% after loading, efficient liquid phase detects eluent composition.
Ethane nitrile content is gradually risen according to liquid phase testing result, until purified polypeptide conjugate main peak is eluted out.Merging is washed
De- liquid, rotary evaporation removes most of solvent, freezes to obtain pure small molecule-polypeptide conjugate (compound 1), HPLC detection levels
More than 90%.
Embodiment 2-7 compounds 2-7 preparation
Method be the same as Example 1, simply connects small molecule and the linking arm (linker) of polypeptide replaces with Beta-alanine respectively
(β Ala), 6-aminocaprolc acid (Aca), PEG1, PEG2, PEG3, the above-mentioned compound as linking arm is first connected with polypeptide respectively
Connect, then be connected with small molecule, obtain compound 2- compounds 7.
The preparation of the compound 8 of embodiment 8
The synthesis of cholesterol monobromo-acetic acid ester (Chol-Br)
Bromoacetic acid 6.95g is weighed successively, and cholesterol 7.73g, EDCHCl 13.43g, DMAP 122mg add 500ml eggplants
In shape bottle, add under DCM 500ml, ice bath and stir, solution is in yellow.30min recession removes ice bath, and 24h, solution are reacted at room temperature
In bronzing.Saturation NaHCO is used successively3, saturation NaCl washing, anhydrous MgSO4Dry.Filled after appropriate concentration with silicagel column wet method
Post loading is purified.First with petroleum ether: ethyl acetate=10: 1 by eluant, eluent after eluent 500ml as being replaced by oil
Ether: ethyl acetate=9: 1, the lower product of elution is evaporated off obtaining white solid 6.3g after solvent, vacuum drying, yield 62%.
Synthesis polypeptide as described in Example 1, then takes polypeptide (＞ 90%) 20mg to be after purification dissolved in 0.3ml first
In DMSO, 0.2ml Chol-Br 3.0mg THF solution is separately added into, adding DIEA 2 with dropper after being well mixed drips, room temperature
3h is reacted, reverse-phase chromatography column separating purification, MALDI-TOF-MS confirmation molecular weight are partly prepared with C4.
Embodiment 9-15 compounds 9-15 preparation
Synthesized micromolecule HT and polypeptide conjugate as described in Example 1 first, then again as described in Example 8 with courage
Sterol is connected, and obtains target compound, MALDI-TOF-MS confirmation molecular weight.
Embodiment 16-45 compounds 16-45 preparation
The method synthesis polypeptide and small molecule HT conjugates of embodiment 1, embodiment 8 and embodiment 9 are pressed respectively, simply will be many
Peptide sequence is changed.
The preparation of the compound 46 of embodiment 46
46.1 NB2The protection of carboxyl and the introducing of linking arm：By NB2Phenyl ring carboxyl is protected with benzyl ester, then in its pyrroles
3 introducings, one carboxyl of ring, to be reacted with linking arm or polypeptide N-terminal.Synthetic route is as follows：
Intermediate it is 2-in-1 into：
Compound 1 (10.0g, 0.04mol) uses 30ml CH2Cl2And 5ml DMF dissolvings, add benzylalcohol after dissolving
(12.85g, 0.12mol), DCC (9.0g, 0.04mol) and 4- pyrollidinopyridine 1.0g, are stirred at room temperature 12 hours, TLC monitorings
Reaction process.Solvent is evaporated off after the completion of reaction, adds ethyl acetate 200ml reactants, filters out DCU.Organic phase uses saturation successively
NaHCO3, 5% citric acid, H2O is washed, anhydrous MgSO4Dry.The crude product of compound 2 purifies [V (petroleum ether) through silica gel column chromatography
: V (ethyl acetate)=7: 2] obtain 6.2g colorless oils, yield 45.76%.
The synthesis of intermediate 3：
4N HCl/EtOAc solution is added in compound 2 (6.2g, 0.02mol), is stirred at room temperature 1 hour, is evaporated reaction
Liquid obtains compound 2 (white solid), is directly used in the next step.
The synthesis of intermediate 6：
Acetone (508ml, 6.90mol), H are added in there-necked flask2O 1000ml, KClO3(120g, 1.10mol).Machinery
Stirring is lower to instill Br2(206ml, 4.00mol), is dripped off for about 1.5 hours.Continue to stir, KCIO colourless to reaction solution3It is completely dissolved,
Reaction is completed.MgO shakings are added in extract and separate, organic phase, anhydrous CaCl is used after washing 3 times2Dry.Vacuum distillation, is collected
Boiling point is 50-51 DEG C of cut, obtains colourless excitant liquid 140.9g.Yield 14.93%.
The synthesis of intermediate 7：
Tert-butyl acetoacetate (5.0ml, 0.03mol) is added in eggplant bottle, absolute ethyl alcohol 25ml, ice bath is cooled to 0 DEG C.
Instilling caustic alcohol (12.3ml, 0.03mol) keeps condition of ice bath to react 15 minutes.Above-mentioned mixed liquor is added to the chemical combination of stirring
In absolute ethyl alcohol/toluene [30ml, V (absolute ethyl alcohol): V (toluene)=2: 1] solution of thing 6 (2.2ml, 0.03mol), room temperature is stirred
Mix 4 hours.Add 2N HC l and be acidified to neutrality, be evaporated off after ethanol adding EtOAc, organic phase is washed three times, anhydrous MgSO4It is dry
It is dry.The crude product of compound 7 purifies [V (petroleum ether): V (ethyl acetate)=7: 2] through silica gel column chromatography and obtains the light yellow liquid of 3.79g
Body.Yield 57.80%.
The synthesis of intermediate 8：
Compound 3 (1.80g, 6.44mmol) is added in eggplant bottle, is dissolved with 30ml toluene.Add N-methylmorpholine
(0.71ml, 6.44mmol), compound 7 (1.52g, 6.44mmol) and p-methyl benzenesulfonic acid 0.08g.Heating reflux reaction 3 hours
After be cooled to room temperature.Remove under reduced pressure and ethyl acetate dissolving is added after solvent, organic phase is washed 3 times, anhydrous MgSO4Dry.Chemical combination
The crude product of thing 8 purifies [V (petroleum ether): V (ethyl acetate)=9: 1] through silica gel column chromatography and obtains 1.91g light yellow liquids.Yield
70.48%.
The synthesis of target compound (compound 9)：
6N HCl/EtOAc solution will be added in intermediate 8, be stirred at room temperature to raw material point and disappear, be evaporated off after solvent adding stone
Oily ether, is placed in refrigerator, obtains light tan powder 1.3g.Yield 83%.
46.2 small molecule NB2With the connection of polypeptide
NB is synthesized according to the method for embodiment 1.22With the conjugate of polypeptide.
Embodiment 47-87 compounds 47-87 preparation
Respectively according to embodiment 46, method synthesis the compound 47-87, MALDI-TOF-MS of embodiment 8 and embodiment 9
Confirm molecular weight.
The preparation of the compound 88 of embodiment 88
88.1 small molecule A12The protection of carboxyl and the introducing (method 1) of linking arm：
The A that route synthesizes carboxy protective is synthesized as follows12, and make its phenolic hydroxyl group into ether, reduce caused by modification to electricity
Property influence and combined using the carboxyl of carboxymethyl with polypeptide N-terminal.
The synthesis of intermediate 2：
5-aminosalicylic acid 0.5g (3.26mmol) 10ml saturations NaHCO are added in eggplant-shape bottle3Dissolving, in suspended
Liquid.Add benzyloxy dicarbonyl chloride 0.61g, 0 DEG C of stirring.Reaction filters out precipitation after terminating, and filtrate uses 4N after washing three times with absolute ether
Hydrochloric acid adjusts PH=2-3.It is extracted with ethyl acetate after acid adjustment three times, ester layer merges, and uses anhydrous Na2SO4It is dried overnight, is evaporated molten
Agent obtains lavender solid, merges with the solid filtered out, obtains intermediate 2.Yield 95%.
The synthesis of intermediate 3：
Intermediate 20.16g is weighed in 50ml eggplant-shape bottles, DMAP 0.006g are added, tert-butyl alcohol 3ml dissolvings are added, in outstanding
Turbid liquid.DCC 0.24g are weighed, are dissolved with the anhydrous THF of 3ml.Above-mentioned solution is added dropwise in eggplant-shape bottle with weighing apparatus pressure funnel, backflow 2
Hour.Solvent evaporated after reaction completely, is dissolved, uses saturation NaHCO afterwards again with ethyl acetate3Wash three times, saturation NaCl solution
Wash three times, anhydrous Na2SO4It is dried overnight.It is evaporated rear crude product and is directly used in the next step.
The synthesis of intermediate 4：
Solid K is added in crude product obtained by upper step2CO30.15g, is dissolved with 3ml 2- butanone, is heated to reflux 30 minutes.
Bromo-acetic acid tert-butyl 0.22g is added in above-mentioned solution, continues to flow back 3 hours.Water 15ml is added after reaction completely, is extracted with chloroform
One time, chloroform layer is washed after twice with 5%NaOH and to wash three times, anhydrous Na with saturation NaCl solution2SO4It is dried overnight.Obtained after being evaporated brown
Color grease.Column chromatographic isolation and purification (petroleum ether: ethyl acetate=8: 1), obtains colorless oil 0.18g.Yield 75%.
The synthesis of intermediate 5：
Weigh 0.2g intermediates 4 and be dissolved in 5ml absolute methanols.Add under 5%Pd/C 0.5g, 50ps i and be catalyzed hydrogen
Change.Reaction filters off 5%Pd/C after 24 hours, is evaporated solution and obtains colorless oil, is directly used in the next step.Yield 50%.
The synthesis of intermediate 6：
Intermediate 50.3g is weighed, is dissolved with 5ml toluene.Add NMM 0.1ml, 2,5- acetyl butyryl 0.23g, to methylbenzene
Sulfonic acid 0.01g, flows back 5 hours.Room temperature is placed after the completion of reaction, solvent is removed under reduced pressure and obtains brownish red grease.Add acetic acid second
Ester 15ml lysates, and wash three times, anhydrous Na with saturation NaCl solution2SO4It is dried overnight.Column chromatographic isolation and purification (petroleum ether
: ethyl acetate=30: 1), obtain colorless oil.Yield 70%.
The synthesis of compound 7：
Above-mentioned gained grease 3ml methanol dissolves, and 1N NaOH 1ml are added dropwise under ice bath.Reaction uses 1N salt after 15 minutes
Acid is neutralized.Remove under reduced pressure and adjust PH=2-3 with 1N hydrochloric acid again after partial solvent.There is white solid precipitation, obtain compound 7.Yield
95%.
88.2 small molecule A12The protection of carboxyl and the introducing (method 2) of linking arm：
The A that route synthesizes carboxy protective is synthesized as follows12, and make its phenolic hydroxyl group into ether, reduce caused by modification to electricity
Property influence and combined using the carboxyl of carboxymethyl with polypeptide N-terminal.The synthetic route compared with 88.1 in synthetic route cause product
Yield is improved significantly.
The synthesis of intermediate 2：
5-NITROSALICYLIC ACID 0.2g is weighed in 50ml eggplant-shape bottles, DMAP 0.006g are added, tert-butyl alcohol 3ml dissolvings are added,
In suspension.DCC 0.24g are weighed, are dissolved with the anhydrous THF of 3ml.Above-mentioned solution is added dropwise in eggplant-shape bottle with weighing apparatus pressure funnel, returned
Stream 2 hours.Solvent evaporated after reaction completely, is dissolved, uses saturation NaHCO afterwards again with ethyl acetate3Wash three times, saturation NaCl it is molten
Liquid washes three times, anhydrous Na2SO4It is dried overnight.Petroleum ether: ethyl acetate=20: 1 crosses post purifying.
The synthesis of intermediate 3：
The 3ml 2- butanone of intermediate 2 dissolves, and adds solid K2CO30.15g, is heated to reflux 30 minutes.In above-mentioned solution
Middle addition bromo-acetic acid tert-butyl 0.22g, continues to flow back 3 hours.Water 15ml is added after reaction completely, is extracted one time with chloroform, chlorine
Imitative layer is washed after twice with 5%NaOH and to wash three times, anhydrous Na with saturation NaCl solution2SO4It is dried overnight.Brown oil is obtained after being evaporated
Thing.Column chromatographic isolation and purification (petroleum ether: ethyl acetate=8: 1), obtains colorless oil 0.18g.Yield 80%.
The synthesis of intermediate 4：
Weigh 0.2g intermediates 3 and be dissolved in 5ml absolute methanols.Add under 10% Pd/C0.02g, 50psi and be catalyzed hydrogen
Change.Reaction filters off 5%Pd/C after 1 hour, is evaporated solution and obtains colorless oil, is directly used in the next step.Yield 98%.
The synthesis of intermediate 5：
Intermediate 40.3g is weighed, is dissolved with 5ml toluene.Add NMM 0.1ml, 2,5- acetyl butyryl 0.23g, to methylbenzene
Sulfonic acid 0.01g, flows back 5 hours.Room temperature is placed after the completion of reaction, solvent is removed under reduced pressure and obtains brownish red grease.Add acetic acid second
Ester 15ml lysates, and wash three times, anhydrous Na with saturation NaCl solution2SO4It is dried overnight.Column chromatographic isolation and purification (petroleum ether
: ethyl acetate=30: 1), obtain colorless oil.Yield 70%.
The synthesis of compound 6：
Above-mentioned gained grease 3ml methanol dissolves, and 1N NaOH 1ml are added dropwise under ice bath.Reaction uses 1N salt after 15 minutes
Acid is neutralized.Remove under reduced pressure and adjust PH=2-3 with 1N hydrochloric acid again after partial solvent.There is white solid precipitation, obtain compound 6.Yield
95%.
88.3 small molecule A12With the preparation of polypeptide conjugate
A is synthesized according to the method for embodiment 1.212With the conjugate of polypeptide.
Embodiment 89-129 compounds 89-129 preparation
Respectively according to embodiment 88, method synthesis the compound 89-129, MALDI-TOF- of embodiment 8 and embodiment 9
MS confirms molecular weight.
The preparation of the compound 130 of embodiment 130
130.1 small molecule mNB2Synthesis：
The NB that route synthesizes carboxy protective is synthesized as follows2, and reacted at its phenolic hydroxyl group position and bromoacetate, by
Ethyl ester is taken off in saponification, and carboxyl is connected with peptide chain.
The synthesis of intermediate 2：
4- nitro-salicylic acids 0.2g is weighed in 50ml eggplant-shape bottles, DMAP 0.006g are added, tert-butyl alcohol 3ml dissolvings are added,
In suspension.DCC 0.24g are weighed, are dissolved with the anhydrous THF of 3ml.Above-mentioned solution is added dropwise in eggplant-shape bottle with weighing apparatus pressure funnel, returned
Stream 4 hours.Solvent evaporated after reaction completely, is dissolved, uses saturation NaHCO afterwards again with ethyl acetate3Wash three times, saturation NaC l
Solution washes three times, anhydrous Na2SO4It is dried overnight.Petroleum ether: ethyl acetate=20: 1 crosses post purifying.
The synthesis of intermediate 3：
The 3ml 2- butanone of intermediate 2 dissolves, and adds solid K2CO30.15g, is heated to reflux 30 minutes.In above-mentioned solution
Bromo-acetic acid tert-butyl 0.22g is added, continues to flow back 3 hours.Water 15ml is added after reaction completely, is extracted one time with chloroform, chloroform
Layer is washed after twice with 5%NaOH and to wash three times, anhydrous Na with saturation NaCl solution2SO4It is dried overnight.Brown oil is obtained after being evaporated.
Column chromatographic isolation and purification (petroleum ether: ethyl acetate=8: 1), obtains colorless oil 0.18g.Yield 80%.
The synthesis of intermediate 4：
Weigh 0.2g intermediates 3 and be dissolved in 5ml absolute methanols.Add under 10%Pd/C0.02g, 50ps i and be catalyzed hydrogen
Change.Reaction filters off 5%Pd/C after 1 hour, is evaporated solution and obtains colorless oil, is directly used in the next step.Yield 98%.
The synthesis of intermediate 5：
Intermediate 40.3g is weighed, is dissolved with 5ml toluene.Add NMM 0.1ml, 2,5- acetyl butyryl 0.23g, to methylbenzene
Sulfonic acid 0.01g, flows back 5 hours.Room temperature is placed after the completion of reaction, solvent is removed under reduced pressure and obtains brownish red grease.Add acetic acid second
Ester 15ml lysates, and wash three times, anhydrous Na with saturation NaC l solution2SO4It is dried overnight.Column chromatographic isolation and purification (oil
Ether: ethyl acetate=30: 1), colorless oil is obtained.Yield 70%.
The synthesis of target compound 6：
Above-mentioned gained grease 3ml methanol dissolves, and 1N NaOH 1ml are added dropwise under ice bath.Reaction uses 1N salt after 15 minutes
Acid is neutralized.Remove under reduced pressure and adjust PH=2-3 with 1N hydrochloric acid again after partial solvent.There is white solid precipitation, obtain compound 6.Yield
95%.
130.2 small molecule mNB2With the preparation of polypeptide conjugate
MNB is synthesized according to the method for embodiment 1.22With the conjugate of polypeptide.
Embodiment 131-171 compounds 131-171 preparation
Respectively according to embodiment 130, method synthesis the compound 131-171, MALDI- of embodiment 8 and embodiment 9
TOF-MS confirms molecular weight.
Embodiment 172-224 compounds 172-224 preparation
Respectively according to embodiment 1, embodiment 8, shown in the method synthesis compound 172-224 of embodiment 9 and embodiment 130
Polypeptide and small molecule conjugates, MALDI-TOF-MS confirmation molecular weight.
The compound of embodiment 225 suppresses the cell-cell fusion activity evaluation (IC of HIV-1 mediations50)
Dye the Cell-Cell Fusion of transfer method detection HIV-1 mediations：HIV-1IIIBH9 cells (the H9/HIV- of infection
1IIIB) marked by a kind of fluorometric reagent Calcein-AM (Molecular Probes, Inc., Eugene, OR), then in 96 holes
37 DEG C add or are not added with test-compound and MT-2 cells (ratio=1: 10) co-cultivation 2h in plate.Test compound is from 250 μ g/
Twice of gradient dilution of ml concentration.Fusion and the reverse fluorescence microscope of cell for the Calcein mark HIV-1 infection do not merged
(Zeiss, Germany) is counted.Calculate IC50Value.
According to the method described above, the table 1 that determination of activity result is seen below.
Table 1：Suppress the cell fusion activity (IC of HIV-1 mediations50)
From the Activity Results of table 1, all small molecule-polypeptide conjugates show suppression HIV-1 cell fusion activities,
Wherein compound 10-15,25-30,39-45,54-59,68-73,81-87,95-101,110-115,124-129,138-143,
151-157,165-171,190-224 suppress HIV fusion-activities and reach low nM levels, with positive control drug T20 (compounds
172) with C34 (compound 173) quite.
Although the embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to disclosed all teachings, various modifications and replacement can be carried out to those details, these change the guarantor in the present invention
Within the scope of shield.The four corner of the present invention is provided by appended claims and its any equivalent.
Claims (7)
1. the salt of the small molecule-polypeptide conjugate or its physiological-toxicity-free shown in Formulas I,
Sm-L1-Xa1EEXd1Xe1KK Xa2EEXd2Xe2KK Xa3EEXd3Xe3KK Xa4EEXd4Xe4KK-L2-Chol
Formulas I
Wherein,
SmFor the micromolecular compound that can be specifically bound with HIV-1 gp41 N-trimer surface hydrophobics pocket region；
L1For what is enabled small molecule to keep space flexibility and combined with target, the linking arm between connection peptide and small molecule, or
Person L1Missing；
EE-KK is the residue combinations to form stable α-helixstructure, respectively positioned at the b of HR sequences, c, f, g, and they are located at spiral shell
The lateral surface of rotation, is contacted with solvent, is not involved in the interaction with target residue, using its side chain it is different electrically between form salt bridge
Act on and formed and stablize α-helixstructure, wherein, E is L-type or D type glutamic acid, and K is L-type or D type lysines；
L2For the linking arm between connecting peptides and cholesterol molecule；
Chol is cholesterol；
Wherein,
Sm is selected from following micromolecular compound：
L1It is selected from：
Beta-alanine,
6-aminocaprolc acid,
NH2-CH2CH2-O-CH2CH2- COOH,
NH2-CH2CH2-O-CH2CH2-O-CH2CH2-COOH,
NH2-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-COOH；
Xa1、Xa2、Xa3、Xa4Can be with identical or different；Xa1、Xa2、Xa3Amino acid selected from following D types or L-type：Alanine, bright ammonia
Acid, isoleucine, valine, serine；Xa4Amino acid selected from following D types or L-type：Alanine, leucine, isoleucine,
Glutamine, valine, serine；
Xd1、Xd2、Xd3、Xd4Can be with identical or different；Xd1、Xd2、Xd4Amino acid selected from following D types or L-type：Alanine, bright ammonia
Acid, isoleucine, valine, serine；Xd3Amino acid selected from following D types or L-type：Alanine, leucine, isoleucine,
Glutamine, valine, serine；
Xe1、Xe2、Xe3、Xe4Can be with identical or different, the amino acid selected from following D types or L-type：Alanine, leucine, different bright ammonia
Acid, valine；
L2For Beta-alanine-cysteine.
2. small molecule-polypeptide conjugate as described below or the salt of its physiological-toxicity-free：
HT----------AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
HT-βAla-AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
HT--Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
HT-2Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
HT--PEG1--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
HT--PEG2--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
HT--PEG3--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
HT----------IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
HT-βAla-IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
HT--Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
HT-2Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
HT--PEG1--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
HT--PEG2--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
HT--PEG3--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
HT----------IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
HT-βAla-IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
HT--Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
HT-2Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
HT--PEG1--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
HT--PEG2--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
HT--PEG3--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
mNB2----------AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
mNB2-βAla-AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
mNB2--Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
mNB2-2Aca--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
mNB2--PEG1--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
mNB2--PEG2--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
mNB2--PEG3--AEELAKK AEELAKK AEELAKK AEELAKK-βAla-C-Chol；
mNB2----------IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
mNB2-βAla-IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
mNB2--Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
mNB2-2Aca--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
mNB2--PEG1--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
mNB2--PEG2--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
mNB2--PEG3--IEELAKK IEELAKK IEELAKK IEELAKK-βAla-C-Chol；
mNB2----------IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
mNB2-βAla-IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
mNB2--Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
mNB2-2Aca--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
mNB2--PEG1--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
mNB2--PEG2--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
mNB2--PEG3--IEELIKK IEELIKK IEELIKK IEELIKK-βAla-C-Chol；
HT----------IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT--Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT-2Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT--PEG1--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT--PEG2--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT--PEG3--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT8----------IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT8-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT8--Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT8-2Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT8--PEG1--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT8--PEG2--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
HT8--PEG3--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
mNB2----------IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
mNB2-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
mNB2--Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
mNB2-2Aca--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
mNB2--PEG1--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
mNB2--PEG2--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol；
mNB2--PEG3--IEELIKK SEELIKK IEEQIKK QEESIKK-βAla-C-Chol。
3. a kind of pharmaceutical composition, it contains small molecule-polypeptide conjugate any one of at least one claim 1-2
Or the salt of its physiological-toxicity-free, and pharmaceutically acceptable carrier or auxiliary material.
4. a kind of HIV fusion inhibitors, its small molecule-polypeptide for containing any one of at least one claim 1-2 is sewed
The salt of compound or its physiological-toxicity-free.
5. the salt of the small molecule-polypeptide conjugate or its physiological-toxicity-free any one of claim 1-2 melts in preparation HIV
Close the purposes in inhibitor.
6. the salt of the small molecule-polypeptide conjugate or its physiological-toxicity-free any one of claim 1-2 is used in preparation
Treat or prevent the purposes in the medicine of HIV relevant disease.
7. purposes according to claim 6, wherein, the HIV relevant disease is AIDS.
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| CN201110368739.4A CN103122025B (en) | 2011-11-21 | 2011-11-21 | Suppress the micromolecule polypeptide conjugate of HIV |
| PCT/CN2012/084859 WO2013075606A1 (en) | 2011-11-21 | 2012-11-20 | Small molecule-polypeptide conjugate inhibiting hiv infection |
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| WO2009155789A1 (en) * | 2008-06-25 | 2009-12-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Polypeptides and derivatives thereof that inhibit hiv infection |
| CN101951958A (en) * | 2007-10-22 | 2011-01-19 | P.安杰莱蒂分子生物学研究所 | Cholesterol derivatives of inhibitors of viral fusion |
| WO2011067302A1 (en) * | 2009-12-01 | 2011-06-09 | Seprox Biotech, S.L. | Topical use of hydroxytyrosol and derivatives for the prevention of hiv infection |
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| EP2377880A3 (en) * | 2008-08-13 | 2012-03-21 | New York Blood Center | Combination therapy of HIV fusion entry inhibitors targeting gp41 |
| WO2011110049A1 (en) * | 2010-03-12 | 2011-09-15 | 中国人民解放军军事医学科学院毒物药物研究所 | Anti-hiv fusion polypeptide and use thereof |
| CN102311487B (en) * | 2010-07-02 | 2018-09-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Polypeptide, composition and the purposes of AntiHIV1 RT activity infection |
-
2011
- 2011-11-21 CN CN201110368739.4A patent/CN103122025B/en not_active Expired - Fee Related
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2012
- 2012-11-20 WO PCT/CN2012/084859 patent/WO2013075606A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101951958A (en) * | 2007-10-22 | 2011-01-19 | P.安杰莱蒂分子生物学研究所 | Cholesterol derivatives of inhibitors of viral fusion |
| WO2009155789A1 (en) * | 2008-06-25 | 2009-12-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Polypeptides and derivatives thereof that inhibit hiv infection |
| WO2011067302A1 (en) * | 2009-12-01 | 2011-06-09 | Seprox Biotech, S.L. | Topical use of hydroxytyrosol and derivatives for the prevention of hiv infection |
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| Publication number | Publication date |
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| WO2013075606A1 (en) | 2013-05-30 |
| CN103122025A (en) | 2013-05-29 |
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