Heptad repeat 1-derived N peptide inhibitors improve broad-spectrum anti-HIV-1 activity

IF 4.8 Q1 MICROBIOLOGY

Current Research in Microbial Sciences Pub Date : 2025-01-01 DOI:10.1016/j.crmicr.2025.100364

Chen Yuan , Jia-Ye Wang , Bu-Yi Wang , Yi-Lin Zhao , Yan Li , Di Li , Hong Ling , Min Zhuang

{"title":"Heptad repeat 1-derived N peptide inhibitors improve broad-spectrum anti-HIV-1 activity","authors":"Chen Yuan , Jia-Ye Wang , Bu-Yi Wang , Yi-Lin Zhao , Yan Li , Di Li , Hong Ling , Min Zhuang","doi":"10.1016/j.crmicr.2025.100364","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>HIV-1 N-peptide inhibitor (NPI) derived from N-terminal heptad-repeat region (HR1) of gp41 can target C-terminal heptad-repeat region (HR2) or the HR1 to interfere with the formation of endogenous six-helix bundle (6HB). However, the NPI is less active than the C-peptide inhibitor. In this study, we reported three HR1-derived NPIs designed by adding fusion peptide proximal region (FPPR) of gp41 or a trimeric motif MTQ into the N36 peptide and then evaluated their anti-HIV-1 activities.</div></div><div><h3>Methods</h3><div>Molecular modeling was performed using Swiss Model. The inhibitory activity of NPIs on HIV-1 was assessed by Env-pseudovirus infection assays and cell-cell fusion assays. Interaction between NPIs and HR2 peptides was evaluated by circular dichroism and Native PAGE.</div></div><div><h3>Results</h3><div>The three newly designed NPIs, FPPR-N36, MTQ-N36, and MTQ-FPPR-N36, exhibited higher anti-HIV-1 activity than N36. The stability of the coiled-coil core formed by three designed NPIs or the 6HB formed by C34 and these NPIs were significantly higher than those of corresponding monomer N36 or isoleucine zipper-engineered trimeric N36 (IZN36). The 50 % inhibitory concentrations (IC<sub>50</sub>) of MTQ-N36 against HIV-1 infection were at a nanomolar level, lower than those of other tested NPIs. The FPPR-N36 could also inhibit infection of HIV-1 strains that were resistant to N36 and IZN36.</div></div><div><h3>Conclusions</h3><div>The three newly designed NPIs had inhibitory activity against HIV-1 infection. Among them, MTQ-N36 exhibited a higher potential to inhibit HIV-1 entry than other peptides, and FPPR-N36 might be a promising candidate NPI for suppressing HIV-1 strains that are resistant to conventional NPIs.</div></div>","PeriodicalId":34305,"journal":{"name":"Current Research in Microbial Sciences","volume":"8 ","pages":"Article 100364"},"PeriodicalIF":4.8000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Research in Microbial Sciences","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2666517425000264","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MICROBIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

HIV-1 N-peptide inhibitor (NPI) derived from N-terminal heptad-repeat region (HR1) of gp41 can target C-terminal heptad-repeat region (HR2) or the HR1 to interfere with the formation of endogenous six-helix bundle (6HB). However, the NPI is less active than the C-peptide inhibitor. In this study, we reported three HR1-derived NPIs designed by adding fusion peptide proximal region (FPPR) of gp41 or a trimeric motif MTQ into the N36 peptide and then evaluated their anti-HIV-1 activities.

Methods

Molecular modeling was performed using Swiss Model. The inhibitory activity of NPIs on HIV-1 was assessed by Env-pseudovirus infection assays and cell-cell fusion assays. Interaction between NPIs and HR2 peptides was evaluated by circular dichroism and Native PAGE.

Results

The three newly designed NPIs, FPPR-N36, MTQ-N36, and MTQ-FPPR-N36, exhibited higher anti-HIV-1 activity than N36. The stability of the coiled-coil core formed by three designed NPIs or the 6HB formed by C34 and these NPIs were significantly higher than those of corresponding monomer N36 or isoleucine zipper-engineered trimeric N36 (IZN36). The 50 % inhibitory concentrations (IC₅₀) of MTQ-N36 against HIV-1 infection were at a nanomolar level, lower than those of other tested NPIs. The FPPR-N36 could also inhibit infection of HIV-1 strains that were resistant to N36 and IZN36.

Conclusions

The three newly designed NPIs had inhibitory activity against HIV-1 infection. Among them, MTQ-N36 exhibited a higher potential to inhibit HIV-1 entry than other peptides, and FPPR-N36 might be a promising candidate NPI for suppressing HIV-1 strains that are resistant to conventional NPIs.

Abstract Image

查看原文本刊更多论文

七肽重复1衍生N肽抑制剂提高广谱抗hiv -1活性

hiv -1 n肽抑制剂（NPI）来源于gp41的n -末端七肽重复区（HR1），可靶向c -末端七肽重复区（HR2）或HR1，干扰内源性六螺旋束（6HB）的形成。然而，NPI的活性低于c肽抑制剂。在这项研究中，我们报道了三个hr1衍生的npi，通过将gp41的融合肽近端区（FPPR）或三聚基序MTQ添加到N36肽中，然后评估了它们的抗hiv -1活性。方法采用Swiss模型进行分子建模。通过env -假病毒感染实验和细胞-细胞融合实验评估npi对HIV-1的抑制活性。通过圆二色性和Native PAGE评价npi与HR2肽的相互作用。结果fpr -N36、MTQ-N36和mtq - fpr -N36的抗hiv -1活性均高于N36。设计的3种npi形成的线圈芯或C34形成的6HB的稳定性显著高于相应的单体N36或异亮氨酸拉链工程三聚体N36 （IZN36）。MTQ-N36对HIV-1感染的50%抑制浓度（IC50）为纳摩尔水平，低于其他npi。fpr -N36还能抑制对N36和IZN36具有抗性的HIV-1毒株的感染。结论新设计的3种npi具有抑制HIV-1感染的活性。其中，MTQ-N36表现出比其他肽更高的抑制HIV-1进入的潜力，fpr - n36可能是抑制对常规NPI具有抗性的HIV-1菌株的有希望的候选NPI。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊