{"title":"2′-β-Methylselenyl nucleos(t)ide analogs as reverse transcriptase inhibitors against diverse HIV mutants","authors":"Yuki Yoshida , Yushi Niimi , Daichi Fushihara , Hideo Katakura , Ryusuke Fukui , Hirotaka Murase , Fumiaki Tomoike , Fumitaka Hashiya , Tsutomu Murakami , Eiichi N. Kodama , Tetsuro Suzuki , Kiyoshi Yasukawa , Yasuaki Kimura , Hiroshi Abe","doi":"10.1016/j.bmc.2024.117813","DOIUrl":null,"url":null,"abstract":"<div><p>Nucleoside reverse transcriptase inhibitors (NRTIs) have been extensively studied as drugs targeting HIV RT. However, the practice or use of approved NRTIs lacking the 3ʹ-hydroxy group often promotes frequent HIV mutations and generates drug-resistance. Here, we describe a novel NRTI with 2<em>′</em>-<em>β</em>-methylselenyl modification. We found that this modification inhibited the DNA elongation reaction by HIV-1 RT despite having a 3<em>′</em>-hydroxy group. Moreover, the conformation of this nucleoside analog is controlled at C3<em>′</em>-endo, a conformation that resists excision from the elongating DNA by HIV RT. Accordingly, the designed analogs exhibited activity against both wild-type HIV and multidrug-resistant HIV mutants.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S096808962400227X/pdfft?md5=ef8bc287dd02ff6f79ff5f4f82c4d359&pid=1-s2.0-S096808962400227X-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S096808962400227X","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs) have been extensively studied as drugs targeting HIV RT. However, the practice or use of approved NRTIs lacking the 3ʹ-hydroxy group often promotes frequent HIV mutations and generates drug-resistance. Here, we describe a novel NRTI with 2′-β-methylselenyl modification. We found that this modification inhibited the DNA elongation reaction by HIV-1 RT despite having a 3′-hydroxy group. Moreover, the conformation of this nucleoside analog is controlled at C3′-endo, a conformation that resists excision from the elongating DNA by HIV RT. Accordingly, the designed analogs exhibited activity against both wild-type HIV and multidrug-resistant HIV mutants.
核苷类逆转录酶抑制剂(NRTIs)作为针对 HIV RT 的药物已被广泛研究。然而,实践或使用已批准的缺乏3ʹ-羟基的NRTIs往往会导致HIV频繁突变并产生耐药性。在这里,我们描述了一种具有 2′-β-甲基硒基修饰的新型 NRTI。我们发现,尽管这种修饰具有 3′-羟基,但它能抑制 HIV-1 RT 的 DNA 延长反应。此外,这种核苷类似物的构象被控制在 C3′-内端,这种构象能阻止 HIV RT 从伸长的 DNA 中切除。因此,所设计的类似物对野生型 HIV 和具有多重耐药性的 HIV 突变体都具有活性。
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.