{"title":"Development of Small-Molecule Anti-HIV-1 Agents Targeting HIV-1 Capsid Proteins","authors":"Takuya Kobayakawa, Masaru Yokoyama, Kohei Tsuji, Sayaka Boku, Masaki Kurakami, Masayuki Fujino, Takahiro Ishii, Yutaro Miura, Soshi Nishimura, Kouki Shinohara, Kenichi Yamamoto, Peter Bolah, Osamu Kotani, Tsutomu Murakami, Hironori Sato, Hirokazu Tamamura","doi":"10.1248/cpb.c23-00618","DOIUrl":null,"url":null,"abstract":"</p><p>The capsid of human immunodeficiency virus type 1 (HIV-1) forms a conical structure by assembling oligomers of capsid (CA) proteins and is a virion shell that encapsulates viral RNA. The inhibition of the CA function could be an appropriate target for suppression of HIV-1 replication because the CA proteins are highly conserved among many strains of HIV-1, and the drug targeting CA, lenacapavir, has been clinically developed by Gilead Sciences, Inc. Interface hydrophobic interactions between two CA molecules <i>via</i> the Trp184 and Met185 residues in the CA sequence are indispensable for conformational stabilization of the CA multimer. Our continuous studies found two types of small molecules with different scaffolds, MKN-1 and MKN-3, designed by <i>in silico</i> screening as a dipeptide mimic of Trp184 and Met185 have significant anti-HIV-1 activity. In the present study, MKN-1 derivatives have been designed and synthesized. Their structure–activity relationship studies found some compounds having potent anti-HIV activity. The present results should be useful in the design of novel CA-targeting molecules with anti-HIV activity.</p>\n<p></p>\n<img alt=\"\" src=\"https://www.jstage.jst.go.jp/pub/cpb/72/1/72_c23-00618/figure/72_c23-00618.png\"/>\n<span style=\"padding-left:5px;\">Fullsize Image</span>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical & pharmaceutical bulletin","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1248/cpb.c23-00618","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
The capsid of human immunodeficiency virus type 1 (HIV-1) forms a conical structure by assembling oligomers of capsid (CA) proteins and is a virion shell that encapsulates viral RNA. The inhibition of the CA function could be an appropriate target for suppression of HIV-1 replication because the CA proteins are highly conserved among many strains of HIV-1, and the drug targeting CA, lenacapavir, has been clinically developed by Gilead Sciences, Inc. Interface hydrophobic interactions between two CA molecules via the Trp184 and Met185 residues in the CA sequence are indispensable for conformational stabilization of the CA multimer. Our continuous studies found two types of small molecules with different scaffolds, MKN-1 and MKN-3, designed by in silico screening as a dipeptide mimic of Trp184 and Met185 have significant anti-HIV-1 activity. In the present study, MKN-1 derivatives have been designed and synthesized. Their structure–activity relationship studies found some compounds having potent anti-HIV activity. The present results should be useful in the design of novel CA-targeting molecules with anti-HIV activity.
人类免疫缺陷病毒1型(HIV-1)的囊膜由囊膜(CA)蛋白的寡聚体组装而成,形成锥形结构,是包裹病毒RNA的病毒外壳。抑制 CA 功能可能是抑制 HIV-1 复制的一个合适靶点,因为 CA 蛋白在许多 HIV-1 株系中高度保守,而针对 CA 的药物来那卡韦已由吉利德科学公司(Gilead Sciences, Inc.两个CA分子之间通过CA序列中的Trp184和Met185残基进行的界面疏水相互作用对于CA多聚体的构象稳定是不可或缺的。我们的连续研究发现,两种具有不同支架的小分子--MKN-1和MKN-3--经硅学筛选设计为Trp184和Met185的二肽模拟物,具有显著的抗HIV-1活性。本研究设计并合成了 MKN-1 衍生物。其结构-活性关系研究发现,一些化合物具有很强的抗 HIV 活性。本研究结果将有助于设计具有抗 HIV 活性的新型 CA 靶向分子。
期刊介绍:
The CPB covers various chemical topics in the pharmaceutical and health sciences fields dealing with biologically active compounds, natural products, and medicines, while BPB deals with a wide range of biological topics in the pharmaceutical and health sciences fields including scientific research from basic to clinical studies. For details of their respective scopes, please refer to the submission topic categories below.
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