CN112851767A - AIDS virus N peptide fusion inhibitor FPPR-N36 and application thereof - Google Patents
AIDS virus N peptide fusion inhibitor FPPR-N36 and application thereof Download PDFInfo
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- CN112851767A CN112851767A CN202110245272.8A CN202110245272A CN112851767A CN 112851767 A CN112851767 A CN 112851767A CN 202110245272 A CN202110245272 A CN 202110245272A CN 112851767 A CN112851767 A CN 112851767A
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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
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- 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
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- 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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- 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
- C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
- C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Abstract
The invention discloses an HIV N peptide fusion inhibitor FPPR-N36 and application thereof, wherein the amino acid sequence of the N peptide fusion inhibitor is shown as SEQ ID NO: 1. The N peptide fusion inhibitor of the invention selects 10 amino acids (HXB2, Env, 536-581) near end (FPPR) of HIV-1gp41N end to be connected with N36(HXB2, Env, 546-581) to ensure that a complete alpha helical structure can be formed. In addition, the invention also tests the inhibition effect of the N-peptide fusion inhibitor on different subtypes of HIV-1 pseudoviruses and cell membrane fusion, the alpha helix proportion and stability of 6-strand helix bundle (6HB) formed by CHR and the capability of interacting with CHR. The results show that compared with the known N36 inhibitor, the N peptide fusion inhibitor of the invention is more stable, has broad spectrum, has stronger HIV-1 inhibiting capability and can inhibit the resistant mutant strains screened by N36 and IZN 36. Therefore, the invention provides more choices with more inhibition potential for the development of anti-HIV drugs.
Description
Technical Field
The invention relates to an HIV N peptide fusion inhibitor and application of the inhibitor in inhibiting HIV-1, belonging to the field of polypeptide inhibitors (medicines).
Background
An HIV is a packaged formThe membrane of the spherical viral particle, the envelope protein is composed of surface glycoprotein gp120 and transmembrane glycoprotein gp 41. gp41 contains an extracellular region, a transmembrane region, and a cytoplasmic region, wherein the extracellular region is critical for promoting membrane fusion. The extracellular domain contains 5 functional domains: fusion Peptide (FP), Fusion Peptide Proximal (FPPR), N-terminal repeat region (NHR), C-terminal heptarepeat region (CHR), and membrane proximal region (MPER). FP contains multiple hydrophobic amino acids and can be inserted into cell membrane to promote formation of 6-strand helix bundle (6HB), FP16(gp 160)512-527) Is the most representative FP core sequence, contains hydrophobic amino acid and has flexible structure and the function of promoting the insertion into cell membrane. FPPR (gp 160)528-541) The structure of the helix can interact with MPER, and the Tm value of gp41 can be increased, thereby increasing the stability of the trimer. NHR and CHR contain multiple seven hydrophobic repeats, divided into a, b, c, d, e, f, g positions in order. Wherein NHR spontaneously forms an alpha helix to form a trimeric coiled-coil (coiled-coil core). The process of HIV invasion into target cells is divided into three steps of (1) gp120 is combined with CD4 through a CD4 binding site (CD4bs), so that the variable regions V1 and V2 are changed, the binding sites of the auxiliary receptors CCR5 and CXCR4 are exposed, the conformation of gp120 is changed after the V3 region is combined with the auxiliary receptors, and the conformation of gp41 is changed, and hydrophobic FP is exposed, inserted and fixed on the surface of host cell membrane; (2)3 CHRs bind to NHR, which spontaneously forms a trimeric coiled-coil, in an antiparallel fashion to form 6 HB; (3) the viral membrane and the host cell membrane are gradually drawn to form a fusion pore (fusion pore), and the viral genome enters the cell through the fusion pore to complete the fusion process. The fusion process of the virus provides a precise target for the research and development of antiviral drugs, the fusion peptide inhibitor is an artificial synthetic peptide derived from gp41 NHR or CHR sequence, acts on the virus or fusion intermediate in a natural state, is combined with the corresponding part of gp41 to form heterologous 6HB, and inhibits the CHR and NHR from forming virus self 6HB, thereby inhibiting membrane fusion and the virus from entering target cells. The mechanism of inhibition by N-peptide inhibitors is divided into two areas, on the one hand, interacting with NHR of gp41 in monomeric or dimeric form to form heterotrimers, thereby interfering with the formation of viral 6 HB. Another aspect is the spontaneous formation of a trimeric coiled-coil, targeting exposed gp41 CHR, formationThe heterogenous 6HB prevents the formation of the 6HB of the virus, the inhibitor in the form of trimer has good solubility, and the inhibition potential is also obviously increased.
Disclosure of Invention
The invention aims to solve the technical problem that resistant mutant strains appear after the existing HIV N peptide inhibitor is screened in vitro, and provides an HIV N peptide fusion inhibitor capable of inhibiting the resistant mutant strains of N36 and IZN 36.
The technical problem to be solved by the invention is realized by the following technical scheme:
the HIV N peptide fusion inhibitor is named as FPPR-N36, and the amino acid sequence of the N peptide fusion inhibitor is shown in SEQ ID NO. 1.
The HIV N peptide fusion inhibitor provided by the invention is characterized in that 10 amino acids (HXB2, Env, 536-581-545) of the near end (FPPR) of the HIV-1gp 41N-terminal fusion peptide are selected to be connected with N36(HXB2, Env, 546-581) so as to ensure that a complete alpha helical structure can be formed. Meanwhile, the invention also detects the inhibition effect of the N-peptide inhibitor on different subtypes of HIV-1 pseudoviruses and cell membrane fusion, the alpha helix proportion and stability of 6-strand helix bundle (6HB) formed by CHR and the interaction capacity with CHR. The results show that compared with the known N36 inhibitor, the N peptide fusion inhibitor of the invention is more stable, has broad spectrum and has enhanced HIV-1 inhibition capability.
The nucleotide sequence for coding the HIV N peptide fusion inhibitor is also in the protection scope of the invention.
Meanwhile, the invention also provides application of the HIV N peptide fusion inhibitor in preparing medicines for inhibiting HIV.
Wherein, preferably, the AIDS virus is HIV-1.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel HIV N peptide fusion inhibitor, named as FPPR-N36, which is obtained by connecting 10 amino acids (HXB2, Env, 536-581) of HIV-1gp 41N-terminal fusion peptide proximal end (FPPR) with N36(HXB2, Env, 546-581) and predicts the structure of the N peptide inhibitor through molecular conformation simulation, thereby ensuring that the N peptide inhibitor can form a complete alpha helix. The inhibition effect of the N peptide inhibitor on different subtype pseudoviruses and cell membrane fusion is detected by a pseudovirus infection inhibition experiment and a cell fusion inhibition experiment. Circular Dichroism (CD) experiments were performed to examine the ratio and stability of the coiled-coil formed by the N-peptide inhibitor and the alpha-helix of 6HB formed by CHR (C34). Native gel electrophoresis (Native-PAGE) measures the amount of 6HB formed by the interaction of the N-peptide inhibitor with CHR. The results show that compared with the known N36 inhibitor, the N peptide fusion inhibitor of the invention is more stable, has broad spectrum and stronger HIV-1 inhibition capability.
Drawings
FIG. 1 is a schematic diagram of the molecular conformation simulation of the N-peptide fusion inhibitor FPPR-N36.
FIG. 2 is a graph showing the results of the inhibitory effect of the N-peptide fusion inhibitor FPPR-N36 on HIV-1 infection with different subtypes of pseudoviruses. N36 is a monomer control.
FIG. 3 is a graph of the results of the coiled coil formation by the N-peptide fusion inhibitor FPPR-N36 and its 6HB helix ratio and stability with C34.
Analyzing alpha helical structure formed by the N peptide inhibitor (A) and stability of the inhibitor (C) by a Circular Dichroism (CD) experiment; the N-peptide inhibitor forms an alpha helix structure (B) of 6HB with C34 and stability (D) of 6 HB.
FIG. 4 is a graph showing the results of 6HB formation by Native gel electrophoresis (Native-PAGE) of the N-peptide fusion inhibitors FPPR-N36 and C34.
The first lane is N36, no band due to positive charge carried out and the removal of the gel plate during electrophoresis; the second lane is C34, and the band is visualized due to the negative charge. The third and fourth lanes are 6HB of the N peptide with C34.
Figure 5 inhibitory effect of peptide N inhibitors on HIVN36 resistant strains.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Example 1
The amino acid sequence of the HIV N peptide fusion inhibitor FPPR-N36 is as follows: Thr-Leu-Thr-Val-Gln-Ala-Arg-Gln-Leu-Leu-Ser-Gly-Ile-Val-Gln-Gln-Gln-Asn-Asn-Leu-Arg-Ala-Ile-Glu-Ala-Gln-Gln-His-Leu-Leu-Gln-Leu-Thr-Val-Trp-Gly-Ile-Lys-Gln-Leu-Gln-Ala-Arg-Ile-Leu (SEQ ID NO: 1).
One, N peptide fusion inhibitor FPPR-N36 conformation mimic
The SWISS Model was used to predict the spatial conformation of the N-peptide fusion inhibitor FPPR-N36, and the molecular conformation of the N-peptide fusion inhibitor FPPR-N36 was analyzed by pymol software. The model of molecular conformation simulation of the N-peptide fusion inhibitor FPPR-N36 is shown in fig. 1, and the structure of the N-peptide inhibitor is predicted by molecular conformation simulation to ensure that a complete alpha helix can be formed.
Two, N peptide fusion inhibitor FPPR-N36 inhibiting effect on HIV pseudovirus infection of different subtypes
Construction of Env pseudovirus: firstly, Env eukaryotic expression plasmid pCDNA3.1-Env and skeleton plasmid psG3 delta Env are extracted. Then eukaryotic cell transfection experiments were performed: human embryonic kidney 293T cells (purchased from ATCC, USA) at 5X 105Spreading in 6-well plate at 37 deg.C and 5% CO2Cultured in a cell culture box. When the cell growth area is 85% -90% of the bottom area of the pore plate, 1 ug of psG3 delta Env and 1 ug of pCDNA3.1-Env fusion protein expression vector are transfected into 293T cells, the transfection reagent used is Lipofectamine LTX (purchased from Invitrogen USA), the instruction of the transfection operation reference reagent, HIV-1 strains and subtypes selected in the experiment are shown in Table 1, and different subtypes of HIV pseudoviruses are constructed according to the above method.
TABLE 1 HIV-1 strain subtypes and tropism selected in the experiment
2. Detection of infection amount of pseudovirus half tissue cells (TCID 50): the pseudovirus was diluted with a culture containing DEAE at a final concentration of 7.5. mu.g/mL. 12.5. mu.L of the pseudovirus constructed above was added to the wells and diluted in 5-fold gradient, and the TZM-bl cells were diluted at 1X 104Spreading in 96-well plate at a density of one/well, and standing at 37 deg.C and 5% CO2Cultured in a cell culture box. After 48h of culture, the same amount of Bright-GloTM Luciferase assay substrate was added, 100. mu.L of the mixture was added to a 96-well black chemiluminescence detection plate, and the plate was placed in a Modulus TM II detector to read the luminescence value.
3. Pseudoviral infection inhibition assay: pseudovirus was diluted to a final concentration of 100-fold TCID 50/well. The N-peptide inhibitor N36 and FPPR-N36 were diluted with a culture medium containing DEAE at a final concentration of 7.5. mu.g/mL. Two-fold gradient dilution was performed, and the diluted N-peptide inhibitors were sequentially added to a 96-well deep-well plate, mixed with the virus in a volume of 1: 1 and mixing. The culture medium was aspirated from the 96-well cell culture plate, 100. mu.L of the incubated virus-N peptide inhibitor mixture was added to the corresponding well, and the TZM-bl cells were plated at 1X 104The cells were plated at a density of one well in a 96-well plate and cultured at 37 ℃ for another 48 hours. Culturing for 48h, adding equal amount of Bright-GloTMAdding 100 mu L of mixed solution into a 96-hole black chemiluminescence detection plate, and adding ModulusTMThe results of the measurement of the luminescence values by the II detector are shown in Table 2 and FIG. 2.
TABLE 2 inhibitory Effect of N-peptide inhibitors on infection by different subtypes of pseudoviruses
4. Cell fusion inhibition assay: first, Env eukaryotic expression plasmids and pSCTZ α, pRev and pSCTZ ω (Carol D.Weiss) were extracted. 1) Transfection of 293T cells: 293T cells (purchased from ATCC in USA) at 5X 105Spreading in 6-well plate at 37 deg.C and 5% CO2Cultured in a cell culture box. When the cell growth area is 85% -90% of the bottom area of the pore plate, 0.1 mu g En is addedv expression plasmid, 1. mu.g pSCTZ. alpha. and 0.6. mu.g pRev into 293T cells using Lipofectamine LTX (ex Invitrogen USA) as a transfection reagent, see reference for the transfection procedures. 2) RC4 cell transfection: RC4 cells (from Oregon university of health and science) were cultured at 5X 105Spreading in 6-well plate at 37 deg.C and 5% CO2Cultured in a cell culture box. To a cell growth area of 85% -90% of the bottom area of the well plate, 1.6 μ g of pSCTZ ω was transfected into RC4 cells using Lipofectamine 2000 (available from Invitrogen, USA) as the transfection reagent, see reagent instructions for transfection procedures. 3) 293T cells and RC4 cells fusion: the transfected 293T cells were cultured at 1X 104The density of individual/well plates was plated in 96-well plates. Putting the mixture into an incubator to incubate for 6 h. 4) After 6h, transfected RC4 cells were cultured at 1X 104Density of individual/well plates were plated in the same 96-well plate. 5) The N peptide fusion inhibitor N36wt and FPPR-N36 were serially diluted in a 96-well deep-well plate and added to a 96-well cell culture plate for overnight incubation. 6) Configuring and operating according to the specification of the GalactoStar kit, and finally putting in ModulusTMThe fluorescence values were read by the II detector and the results are shown in Table 3.
TABLE 3 inhibitory Effect of N-peptide inhibitors on HIV Env cell-cell fusion experiments
Alpha helix formation and stability of triple, N-peptide fusion inhibitor FPPR-N36
Circular dichroism experiments (Circular dichroism, CD): the N peptide was dissolved in ultrapure water, the C peptide was dissolved in PBS buffer pH7, 12000r/min, and the mixture was centrifuged for 10min without insoluble matter. mu.L of 6M guanidine hydrochloride was diluted 10-fold and denatured in 1. mu.L of stock solution, and protein A280 was read with NanoDrop 2000 for computational quantification of N-and C-peptides. Stock solutions of the N-peptide inhibitors FPPR-N36 or N36wt and C34 were diluted with peptide inhibitor buffer containing 20mM sodium phosphate salt and 0.2M sodium chloride to prepare a mixture at a final concentration of 10. mu.M in a final volume of 200. mu.L, and incubated at 37 ℃ for 30 min. Detecting with Chirascan circular dichroism instrument at 20 deg.C, wherein the scanning range is 300-190nm, the bandwidth is 1.0nm, the reaction time is 4.0s, and the scanning speed is 5 nm/min. The background value of buffer is removed to obtain a graph of alpha helix. The alpha helix conformation is characterized by negative peaks at 208nm and 222 nm. The formation of alpha helices was detected by negative values at 208 and 222 nm. The thermal stability of the peptide was measured by raising the temperature from 4 ℃ to 95 ℃ at a rate of 1 ℃/min at a wavelength of 222nm, smoothing the obtained curve, and calculating the Tm value, which is the midpoint temperature, in direct proportion to the stability of the polypeptide. Reverse denaturation at 95-4 deg.C. The results are shown in FIG. 3.
Four, 6HB formation between N peptide fusion inhibitor FPPR-N36 and C34
Native-PAGE experiments: stock solutions of the N-peptide inhibitors FPPR-N36 or N36wt and C34 were prepared in peptide inhibitor buffer containing 20mM sodium phosphate and 0.2M sodium chloride at a concentration of 40. mu.M in a final volume of 25. mu.L and incubated in a water bath at 37 ℃ for 30 min. mu.L of 6 Xnon-reduced Loading Buffer (0.35M Tris-HCl pH6.8, 30% glycerol, 10% SDS, 0.012% bromophenol blue) was added to 20. mu.L of the above treated sample and subjected to electrophoresis at 125V for 2 hours. After the electrophoresis was completed, the gel was taken out and placed in Coomassie Brilliant blue R-250, followed by staining for 2 hours with shaking in an air shaker. And after dyeing is finished, putting the obtained product into a decoloring solution, and putting the obtained product into an air oscillator at room temperature for shaking and decoloring until the decoloring is complete. The photographs were taken with a GIS-2010 gel imaging analysis system. The results are shown in FIG. 4.
Inhibitory Effect of N-peptide fusion inhibitor on HIV N36-resistant Strain
Pseudo viruses are constructed by two envelopes (2012JBC) of mutant strains JR-Q577R E648K and JR-E560K Q577R T641I resistant to N peptide fusion inhibitors N36 and IZN36 screened in vitro by using HIV-1JR wild strains in earlier researches, and a pseudo virus inhibition experiment is carried out by the method. As a result, it was found that the N-peptide fusion inhibitor FPPR-N36 can effectively inhibit two mutant strains, IC thereof504.08. mu.M and 3.65. mu.M, respectively.
Sequence listing
<110> Harbin university of medicine
<120> HIV N peptide fusion inhibitor FPPR-N36 and application thereof
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 46
<212> PRT
<213> artificial sequence
<400> 1
Thr Leu Thr Val Gln Ala Arg Gln Leu Leu Ser Gly Ile Val Gln Gln
1 5 10 15
Gln Asn Asn Leu Leu Arg Ala Ile Glu Ala Gln Gln His Leu Leu Gln
20 25 30
Leu Thr Val Trp Gly Ile Lys Gln Leu Gln Ala Arg Ile Leu
35 40 45
Claims (4)
1. An HIV N peptide fusion inhibitor is named as FPPR-N36 and is characterized in that the amino acid sequence of the N peptide fusion inhibitor is shown as SEQ ID NO. 1.
2. A nucleotide sequence encoding the hiv N-peptide fusion inhibitor of claim 1.
3. The use of the HIV N-peptide fusion inhibitor of claim 1 in the preparation of a medicament for inhibiting HIV.
4. The use of claim 3, wherein the HIV is HIV-1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100098724A1 (en) * | 2008-10-16 | 2010-04-22 | Shibo Jiang | Immunoenhacer-linked oligomeric hiv vaccines |
| CN102883740A (en) * | 2010-05-03 | 2013-01-16 | 纽约血库公司 | Bifunctional molecules for inactivating HIV and blocking HIV |
| WO2013127300A1 (en) * | 2012-02-28 | 2013-09-06 | 中国人民解放军军事医学科学院毒物药物研究所 | Polypeptide for use in inhibiting hiv, pharmaceutical composition of the polypeptide, and use thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100098724A1 (en) * | 2008-10-16 | 2010-04-22 | Shibo Jiang | Immunoenhacer-linked oligomeric hiv vaccines |
| CN102883740A (en) * | 2010-05-03 | 2013-01-16 | 纽约血库公司 | Bifunctional molecules for inactivating HIV and blocking HIV |
| EP2566493A1 (en) * | 2010-05-03 | 2013-03-13 | New York Blood Center, Inc. | Bifunctional molecules for inactivating hiv and blocking hiv |
| WO2013127300A1 (en) * | 2012-02-28 | 2013-09-06 | 中国人民解放军军事医学科学院毒物药物研究所 | Polypeptide for use in inhibiting hiv, pharmaceutical composition of the polypeptide, and use thereof |
Non-Patent Citations (3)
| Title |
|---|
| SHUWEN LIU 等: ""Different from the HIV fusion inhibitor C34, the anti-HIV drug Fuzeon (T-20) inhibits HIV-1 entry by targeting multiple sites in gp41 and gp120"", 《J BIOL CHEM》 * |
| SU,S 等: ""Chain K, HIV-1 gp41 NHR"", 《GENBANK》 * |
| 邵继平 等: ""基于gp41的HIV亚单位疫苗研究进展"", 《细胞与分子免疫学杂志》 * |
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