Characterization of novel HIV fusion-inhibitory lipopeptides with the M-T hook structure

IF 2.6 4区医学 Q3 IMMUNOLOGY

Microbes and Infection Pub Date : 2024-11-01 DOI:10.1016/j.micinf.2024.105366

Xiuzhu Geng , Xiaohui Ding , Yuanmei Zhu , Huihui Chong , Yuxian He

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引用次数: 0

Abstract

Combination antiretroviral therapy (cART) has significantly improved the survival of HIV-infected individuals, but long-term treatment can cause side-effects and drug resistance; thus, the development of new antivirals is of importance. We previously identified an M-T hook structure and accordingly designed short-peptide fusion inhibitor 2P23, which mainly targets the gp41 pocket site and displays potent, broad-spectrum anti-HIV activity. In this study, we continuingly characterized the amino acid sequences of peptide and lipopeptide-based inhibitors containing the M-T hook residues. Among a group of lipopeptides, stearic acid (C18)-modified LP-25 and LP-29 exhibited greatly improved inhibitions against divergent HIV-1 subtypes and drug-resistant mutants. LP-25 and LP-29 were evaluated in rhesus macaques, and the ex vivo inhibition data demonstrated their potent, long-lasting in vivo anti-HIV activity, with LP-25 much better than LP-29. Both the lipopeptides displayed high α-helicity, thermostability and binding ability to a target-mimic peptide, and they were metabolically stable when treated with high temperature, proteolytic enzymes, human or monkey sera and human liver microsomes. Therefore, our studies have provided critical information for understanding the structure-activity relationship of HIV fusion inhibitors with the M-T hook structure and offered novel candidates for drug development.

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具有 M-T 钩结构的新型 HIV 融合抑制脂肽的特征。

联合抗逆转录病毒疗法（cART）大大提高了艾滋病毒感染者的生存率，但长期治疗会产生副作用和耐药性；因此，开发新的抗病毒药物非常重要。我们之前确定了 M-T 钩结构，并据此设计了短肽融合抑制剂 2P23，它主要针对 gp41 口袋位点，具有强效、广谱的抗 HIV 活性。在这项研究中，我们继续对含有 M-T 钩残基的肽类和脂肽类抑制剂的氨基酸序列进行了表征。在一组脂肽中，经硬脂酸（C18）修饰的 LP-25 和 LP-29 对不同 HIV-1 亚型和耐药突变体的抑制作用大大提高。在猕猴体内对 LP-25 和 LP-29 进行了评估，其体内外抑制数据表明，它们具有强效、持久的体内抗 HIV 活性，其中 LP-25 的效果比 LP-29 更好。这两种脂肽都显示出很高的α-螺旋度、热稳定性和与目标模拟肽的结合能力，而且在高温、蛋白水解酶、人或猴血清和人肝微粒体的作用下，它们的代谢都很稳定。因此，我们的研究为理解具有 M-T 钩结构的 HIV 融合抑制剂的结构-活性关系提供了关键信息，并为药物开发提供了新的候选物。

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来源期刊

Microbes and Infection 医学-病毒学

CiteScore

12.60

自引率

1.70%

发文量

审稿时长

40 days

期刊介绍： Microbes and Infection publishes 10 peer-reviewed issues per year in all fields of infection and immunity, covering the different levels of host-microbe interactions, and in particular: the molecular biology and cell biology of the crosstalk between hosts (human and model organisms) and microbes (viruses, bacteria, parasites and fungi), including molecular virulence and evasion mechanisms. the immune response to infection, including pathogenesis and host susceptibility. emerging human infectious diseases. systems immunology. molecular epidemiology/genetics of host pathogen interactions. microbiota and host "interactions". vaccine development, including novel strategies and adjuvants. Clinical studies, accounts of clinical trials and biomarker studies in infectious diseases are within the scope of the journal. Microbes and Infection publishes articles on human pathogens or pathogens of model systems. However, articles on other microbes can be published if they contribute to our understanding of basic mechanisms of host-pathogen interactions. Purely descriptive and preliminary studies are discouraged.