CN113061190B - HIV N peptide fusion peptide inhibitor MTQ-N36 and application thereof - Google Patents
HIV N peptide fusion peptide inhibitor MTQ-N36 and application thereof Download PDFInfo
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Abstract
The invention discloses an HIV N peptide fusion inhibitor MTQ-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 20 amino acids (12-31) in MTQ to be connected with N36 (HXB 2, env, 546-581) of HIV-1, and ensures that a complete alpha spiral structure can be formed. In addition, the invention also detects 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 a 6-strand helix bundle (6 HB) formed by CHR and the interaction capacity with CHR. The results show that the N-peptide fusion inhibitor of the invention is more stable and has a broad spectrum and enhanced HIV-1 inhibiting ability compared with the known IZN36 inhibitor. Therefore, the invention provides more choices with inhibition potential for the development of anti-HIV drugs.
Description
Technical Field
The invention relates to an N-peptide fusion inhibitor, and also relates to an application of the inhibitor in inhibiting HIV-1, belonging to the technical field of polypeptide inhibitors (drugs).
Background
The Human Immunodeficiency Virus (HIV) is a spherical virion with an envelope composed of a surface glycoprotein gp120 and a 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 heptad (NHR), C-terminal heptad (CHR), and membrane proximal region (MPER). FP contains a plurality of hydrophobic amino acids and can be inserted into cell membranes to promote the formation of 6HB; NHR and CHR contain several seven hydrophobic repeats, each of which has amino acid sequence divided into a, b, c, d, e, f and g positions. Wherein NHR spontaneously forms an alpha helix, constituting a trimeric coiled-coil (coiled-coil core). The process of HIV entry into target cells is divided into three steps: (1) gp120 binds to CD4 through a CD4 binding site (CD 4 bs), so that the variable regions V1 and V2 are changed, the binding sites of the auxiliary receptors CCR5 and CXCR4 are exposed, and the conformation of gp120 is changed after the V3 region is combined with the auxiliary receptors, so that the conformation of gp41 is changed, and hydrophobic FP is exposed, inserted and fixed on the surface of a host cell membrane; (2) 3 CHR bind to NHR, which spontaneously forms a trimeric coiled-coil, in an antiparallel manner to form 6HB; (3) The viral envelope 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 artificially synthesized peptide derived from gp41 NHR or CHR sequence, acts on natural virus or fusion intermediate, combines with corresponding part of gp41 to form heterologous 6HB, and inhibits CHR and NHR from forming virus self 6HB, thereby inhibiting membrane fusion and virus invasion of target cells. The inhibition mechanism of N-peptide inhibitors is divided into two aspects, on one hand, the interaction between monomer or dimer and NHR of gp41 forms heterotrimeric coiled-coil, thereby interfering with the formation of virus 6HB. On the other hand, the inhibitor spontaneously forms a trimer coiled coil to target exposed gp41 CHR to form heterologous 6HB, so that the formation of the 6HB of the virus is prevented, the solubility of the trimer-form inhibitor is good, and the inhibition potential is also obviously increased.
In 2002, the International Intellectual Property Organization (WIPO) disclosed a group of trimerized polypeptides (WO/2002/024735) comprising IZN17, IZN23, IZN36, into which a trimerization motif Isoleucine Zipper (IZ) was introduced on the basis of monomeric inhibitors. IZ has 4 groups of seven-repeated sequences similar to Ile-Glu-Lys-Lys-Ile-Glu-Ala (d-e-f-g-a-b-c), the charged amino acid residues form good electrostatic interaction with the amino acid residues of the adjacent helix, and the glutamic acid Glu at the b position forms a salt bridge with the lysine Lys at the f position in the same helix, thus improving the stability of the coiled-coil. These properties allow the structure of the inhibitor introduced into IZ to be a stable trimeric coiled coil, with the inhibitory effect on the nanomolar scale (Eckert DM, kim PS. Design of the patent inhibitors of HIV-1entry from the gp41N-peptide region. Proc Natl Acad Sci U SA.2001;98 (20): 11187-11192.).
In 2009, WIPO disclosed a trimerization modif MTQ whose amino acid sequence was centered on four heptad sequences: glu-Ile-Ala-Lys-Ile-Lys-Glu-Glu-Gln-Ala-Lys-Ile-Lys-Glu-Lys-Ile-Ala-Glu-Ile-Glu-Lys-Arg-Ile-Ala-Glu-Ile-Glu-Lys, seven amino acid residues of the above seven-repeating sequence are sequentially represented by g-a-b-c-d-e-f, and isoleucine (Ile) is introduced into positions a and d to form a hydrophobic core of a coiled coil; glutamine (Gln) is introduced into a position a of the second heptad repetitive sequence, so that the polymerization number and the polymerization direction of the coiled-coil are facilitated, and a parallel coiled-coil structure is formed; glu-Lys-Glu at the g-c-f position is combined to form a spiral inner salt bridge, so that the stability of a trimerization module is improved. Arginine (Arg) at the g position of the 4 th heptad sequence has important significance in the formation of tripolymer and improves the trimerization capacity of the module. Ile-Lys-Glu before the g-position of the N-terminal and Arg-Ile-Ala after the f-position of the C-terminal are "protective amino acids", and the internal amino acids form a coiled coil structure of a heptad sequence. The Gly-Gly-Ser-Gly-Gly sequence at the upstream of Ile-Lys-Glu at the N terminal of the module is a flexible connecting sequence (linker) between the module and the target protein, can keep the relative independence of the structure of the trimerization module and the target protein, and can also be used as a protective amino acid at the N terminal to increase the spiral component in the coiled spiral and ensure that the spiral structure is more stable. Therefore, the invention selects an appropriate length of MTQ to link to N36, ensuring that the synthetic N-peptide inhibitor can form a complete alpha helix structure.
Disclosure of Invention
The invention aims to solve the technical problems that the existing N peptide inhibitor has poor monomer solubility, is easy to aggregate, has low bioavailability, has a monomer inhibition effect only in a micromolar level and the like, and provides an N peptide fusion inhibitor which is difficult to aggregate, is more stable and has a stronger HIV-1 inhibition effect, and is named as MTQ-N36.
The technical problem to be solved by the invention is realized by the following technical scheme:
the N peptide fusion inhibitor of the AIDS virus is named as MTQ-N36, and the amino acid sequence of the N peptide fusion inhibitor is shown as SEQ ID NO. 1.
The N peptide fusion inhibitor provided by the invention selects 20 amino acids (12-31) in MTQ to be connected with N36 (HXB 2, env, 546-581) of HIV-1, so as to ensure that a complete alpha helical structure can be formed, and simultaneously, the inhibition effect of the MTQ-N36 fusion inhibitor on different subtype pseudoviruses and cell membrane fusion, the alpha helical proportion and stability of a 6-strand helical bundle (6 HB) formed by CHR and the interaction capacity with CHR are also detected. The results show that the N-peptide fusion inhibitor of the invention is more stable and has a broad spectrum and enhanced HIV-1 inhibiting ability compared with the known IZN36 inhibitor.
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 MTQ-N36, which is obtained by connecting 20 amino acids (12-31) in MTQ selected by the N peptide fusion inhibitor with N36 (HXB 2, env, 546-581) of HIV-1. The pseudovirus infection inhibition experiment and the cell fusion inhibition experiment detect the inhibition effect of the N peptide inhibitor on different subtype pseudoviruses and cell membrane fusion. Circular Dichroism (CD) experiments were performed to examine the coiled-coil formation of N-peptide inhibitors and the alpha-helix ratio and stability of 6HB formed by CHR (C34). Native-PAGE (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 IZN36 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 MTQ-N36.
FIG. 2 is a graph showing the results of the inhibitory effect of the N-peptide fusion inhibitor MTQ-N36 on HIV-1 different subtype pseudovirus infection. IZN36 is a trimer control.
FIG. 3 is a graph of the results of the coiled-coil formation by N-peptide fusion inhibitors and their ratio and stability to C34 to form a 6HB helix.
Analyzing alpha helical structure formed by the N peptide fusion inhibitor (A) and stability of the inhibitor (C) by a Circular Dichroism (CD) experiment; the N-peptide fusion inhibitor forms an alpha helix structure (B) of 6HB and stability (D) of 6HB with C34.
FIG. 4 is a graph showing the results of 6HB formation by Native gel electrophoresis (Native-PAGE) of the N-peptide fusion inhibitor and C34.
The first lane is N36, which is not a band because it carries a positive charge and is removed from the gel plate during electrophoresis; the second lane is C34, and the band is visualized due to the negative charge. Lanes three, four and five show 6HB formed by the N-peptide fusion inhibitor with C34.
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 substitutions are intended to be within the scope of the invention.
Example 1
The amino acid sequence of the N peptide fusion inhibitor MTQ-N36 is as follows:
Lys-Ile-Lys-Glu-Glu-Gln-Ala-Lys-Ile-Lys-Glu-Lys-Ile-Ala-Glu-Ile-Glu-Lys-Arg-Ile-Ser-Gly-Ile-Val-Gln-Gln-Gln-Asn-Asn-Leu-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)。
1. n-peptide fusion inhibitor conformation mimic
The SWISS Model was used to predict the spatial conformation of the N-peptide inhibitor and the molecular conformation of the N-peptide inhibitor was analyzed by pymol software. The pattern of molecular conformation simulation of the N-peptide fusion inhibitor MTQ-N36 is shown in fig. 1, and the structure of the N-peptide fusion inhibitor is predicted by molecular conformation simulation to ensure that a complete α -helix can be formed.
2. Inhibitory Effect of N-peptide fusion inhibitors on infection with different subtypes of HIV pseudoviruses
Construction of env pseudoviruses: firstly, env eukaryotic expression plasmid 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 10 5 Density of each well was laid in 6-well plates, incubated at 37 ℃ and 5% CO 2 The cell culture box of (2). When the cell growth area was 85% -90% of the bottom area of the well plate, 1. Mu.g of Env eukaryotic expression plasmid was transfected into 293T cells using Lipofectamine LTX (from Invitrogen USA) as a transfection reagent, see reagent manual for transfection procedures. HIV-1 strains and subtypes selected in the experiment are shown in Table 1, and HIV pseudoviruses of different subtypes are constructed according to the method.
HIV-1 strains and subtypes selected in the experiment of Table 1
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 10 4 The density of each well is laid in a 96-well plate and placed at 37 DEG C、5％CO 2 Cultured 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 times TCID 50/well. The N-peptide inhibitors IZN36 and MTQ-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 10 4 The cells were plated in 96-well plates at a density of one well and incubated at 37 ℃ for an additional 48h. Culturing for 48h, adding equal amount of Bright-Glo TM Adding 100 mu L of mixed solution into a 96-hole black chemiluminescence detection plate, and adding Modulus TM The II detector reads the luminescence value, and the result is shown in Table 2 and FIG. 2.
TABLE 2 inhibitory Effect of N-peptide inhibitors on infection by HIV pseudoviruses of different subtypes
4. Cell fusion inhibition assay: first, env eukaryotic expression plasmids and pSCTZ α, pRev and pSCTZ ω (Carol D.Weiss) were extracted. 1) 293T cell transfection: 293T cells (purchased from ATCC, USA) at 5X 10 5 Density of each well in 6-well plate, placing at 37 deg.C, 5% CO 2 The cell culture box of (2). When the cell growth area was 85% -90% of the bottom area of the well plate, 0.1. Mu.g of Env expression plasmid, 1. Mu.g of pSCTZ. Alpha. And 0.6. Mu.g of pRev were transfected into 293T cells using Lipofectamine LTX (from Invitrogen USA) as the transfection protocol reference. 2) RC4 cell transfection: RC4 cells (from Oregon university of health and science) at 5X 10 5 Density of each well was laid in 6-well plates, incubated at 37 ℃ and 5% CO 2 Cultured in a cell culture box. To the cell growth area of the bottom surface of the pore plateBetween 85% and 90% of the volume, 1.6. Mu.g pSCTZ. Omega. Was transfected into RC4 cells using Lipofectamine 2000 (ex Invitrogen USA) as the transfection reagent, reference reagent for transfection procedures. 3) 293T cells and RC4 cells fusion: the transfected 293T cells were cultured at 1X 10 4 The density of individual/well plates was plated in 96-well plates. Putting into an incubator for incubation for 6h. 4) After 6h, transfected RC4 cells were cultured at 1X 10 4 Density of individual/well plates were plated in the same 96-well plate. 5) N peptide inhibitors IZN36 and MTQ-N36 are serially diluted in a 96-well deep-well plate, added into a 96-well cell culture plate and incubated overnight. 6) Configuring and operating according to the specification of the GalactoStar kit, and finally putting in Modulus TM The 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 cell-cell fusion experiments
3. Alpha helix formation and stability of N-peptide inhibitors
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 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. The peptide inhibitor buffer was mixed with a stock solution of IZN36, MTQ-N36 and C34 to prepare a mixture of 10. Mu.M to 200. Mu.L in final volume, and incubated at 37 ℃ for 30min. Detecting with Chirascan circular dichroism chromatograph 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 5nm/min. The background value of buffer is removed to obtain a plot of the alpha helix. The alpha helical 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.
4. Case of 6HB formation with C34 by N-peptide inhibitor
Native-PAGE experiments: stock solutions of the N-peptide inhibitors IZN36 or MTQ-N36 and C34 were made up to a concentration of 40. Mu.M in a final volume of 25. Mu.L using peptide inhibitor buffer containing 20mM sodium phosphate and 0.2M sodium chloride and incubated in a water bath at 37 ℃ for 30min. 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 125V,2h electrophoresis. 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.
Sequence listing
<110> Harbin university of medicine
<120> HIV N peptide fusion peptide inhibitor MTQ-N36 and application thereof
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 56
<212> PRT
<213> artificial sequence
<400> 1
Lys Ile Lys Glu Glu Gln Ala Lys Ile Lys Glu Lys Ile Ala Glu Ile
1 5 10 15
Glu Lys Arg Ile Ser Gly Ile Val Gln Gln Gln Asn Asn Leu Leu Arg
20 25 30
Ala Ile Glu Ala Gln Gln His Leu Leu Gln Leu Thr Val Trp Gly Ile
35 40 45
Lys Gln Leu Gln Ala Arg Ile Leu
50 55
Claims (3)
1. An HIV N peptide fusion inhibitor is named as MTQ-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 nucleic acid 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-1.
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| US6150088A (en) * | 1997-04-17 | 2000-11-21 | Whitehead Institute For Biomedical Research | Core structure of gp41 from the HIV envelope glycoprotein |
| WO2003104262A2 (en) * | 2002-06-10 | 2003-12-18 | Mymetics Corporation | Gp41 peptides and methods based-thereon for inhibiting hiv fusion to target cells |
| CN101709305A (en) * | 2009-11-25 | 2010-05-19 | 哈尔滨医科大学 | Expression method of a high secretory tripolymer protein |
| CN101724027A (en) * | 2009-11-24 | 2010-06-09 | 哈尔滨医科大学 | Protein trimerization module and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6747126B1 (en) * | 1998-07-30 | 2004-06-08 | Whitehead Institute For Biomedical Research | Peptide inhibitors of HIV entry |
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|---|---|---|---|---|
| US6150088A (en) * | 1997-04-17 | 2000-11-21 | Whitehead Institute For Biomedical Research | Core structure of gp41 from the HIV envelope glycoprotein |
| WO2003104262A2 (en) * | 2002-06-10 | 2003-12-18 | Mymetics Corporation | Gp41 peptides and methods based-thereon for inhibiting hiv fusion to target cells |
| CN101724027A (en) * | 2009-11-24 | 2010-06-09 | 哈尔滨医科大学 | Protein trimerization module and application thereof |
| CN101709305A (en) * | 2009-11-25 | 2010-05-19 | 哈尔滨医科大学 | Expression method of a high secretory tripolymer protein |
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