Lenacapavir的发现：每年两次用于HIV-1治疗和暴露前预防的一流衣壳抑制剂。

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-10-01 DOI:10.1021/acs.jmedchem.5c01625

Eda Canales,Winston Tse,Scott D Schroeder,Chien-Hung Chou,Qi Liu,Jennifer Zhang,Scott E Lazerwith,Philip Morganelli,Roland D Saito,Gediminas Brizgys,Jiayao Li,Qiaoyin Wu,Michael Graupe,Randall L Halcomb,Manoj Desai,Carina Cannizzaro,Eric Hu,Jason K Perry,Armando G Villaseñor,John R Somoza,Ryan D Ferrao,S Swaminathan,Jim Zheng,Bing Lu,Judy Mwangi,Kelly Wang,Raju Subramanian,Bill J Smith,Gerry Rhodes,William Rowe,Dorothea Sauer,Latesh Lad,Giuseppe A Papalia,Sheila Clancy,George J Stepan,Helen Yu,Roman Sakowicz,Bing Shi,Gavin Carr,Rujuta A Bam,Luong K Tsai,Eric Singer,Derek Hansen,Andrew Mulato,Stephen R Yant,Tomas Cihlar,John O Link

{"title":"Lenacapavir的发现：每年两次用于HIV-1治疗和暴露前预防的一流衣壳抑制剂。","authors":"Eda Canales,Winston Tse,Scott D Schroeder,Chien-Hung Chou,Qi Liu,Jennifer Zhang,Scott E Lazerwith,Philip Morganelli,Roland D Saito,Gediminas Brizgys,Jiayao Li,Qiaoyin Wu,Michael Graupe,Randall L Halcomb,Manoj Desai,Carina Cannizzaro,Eric Hu,Jason K Perry,Armando G Villaseñor,John R Somoza,Ryan D Ferrao,S Swaminathan,Jim Zheng,Bing Lu,Judy Mwangi,Kelly Wang,Raju Subramanian,Bill J Smith,Gerry Rhodes,William Rowe,Dorothea Sauer,Latesh Lad,Giuseppe A Papalia,Sheila Clancy,George J Stepan,Helen Yu,Roman Sakowicz,Bing Shi,Gavin Carr,Rujuta A Bam,Luong K Tsai,Eric Singer,Derek Hansen,Andrew Mulato,Stephen R Yant,Tomas Cihlar,John O Link","doi":"10.1021/acs.jmedchem.5c01625","DOIUrl":null,"url":null,"abstract":"The HIV capsid is essential to the virus lifecycle, making it a promising target for therapeutic intervention. In 2006, a screening campaign was initiated to identify small molecules capable of disrupting the protein-protein interactions required for self-assembly of the 1500 capsid monomers that form the 37 MDa fullerene cone-shaped capsid. Numerous compound design cycles over many years were undertaken to discover the complex structural elements that together afford the multistage HIV capsid inhibitor lenacapavir. Lenacapavir is the most potent (HIV-1 EC50 = 105 pM) and longest-acting HIV antiviral to date, with a unique twice-yearly dosing regimen. Clinically, lenacapavir has demonstrated robust efficacy for both HIV-1 treatment and prevention, and, remarkably, achieved 100% protection in women for the first time. These findings represent a significant advancement in treatment and prevention of HIV-1 infection, offering the potential to profoundly impact the global course of the HIV epidemic.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"21 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of Lenacapavir: First-in-Class Twice-Yearly Capsid Inhibitor for HIV-1 Treatment and Pre-exposure Prophylaxis.\",\"authors\":\"Eda Canales,Winston Tse,Scott D Schroeder,Chien-Hung Chou,Qi Liu,Jennifer Zhang,Scott E Lazerwith,Philip Morganelli,Roland D Saito,Gediminas Brizgys,Jiayao Li,Qiaoyin Wu,Michael Graupe,Randall L Halcomb,Manoj Desai,Carina Cannizzaro,Eric Hu,Jason K Perry,Armando G Villaseñor,John R Somoza,Ryan D Ferrao,S Swaminathan,Jim Zheng,Bing Lu,Judy Mwangi,Kelly Wang,Raju Subramanian,Bill J Smith,Gerry Rhodes,William Rowe,Dorothea Sauer,Latesh Lad,Giuseppe A Papalia,Sheila Clancy,George J Stepan,Helen Yu,Roman Sakowicz,Bing Shi,Gavin Carr,Rujuta A Bam,Luong K Tsai,Eric Singer,Derek Hansen,Andrew Mulato,Stephen R Yant,Tomas Cihlar,John O Link\",\"doi\":\"10.1021/acs.jmedchem.5c01625\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The HIV capsid is essential to the virus lifecycle, making it a promising target for therapeutic intervention. In 2006, a screening campaign was initiated to identify small molecules capable of disrupting the protein-protein interactions required for self-assembly of the 1500 capsid monomers that form the 37 MDa fullerene cone-shaped capsid. Numerous compound design cycles over many years were undertaken to discover the complex structural elements that together afford the multistage HIV capsid inhibitor lenacapavir. Lenacapavir is the most potent (HIV-1 EC50 = 105 pM) and longest-acting HIV antiviral to date, with a unique twice-yearly dosing regimen. Clinically, lenacapavir has demonstrated robust efficacy for both HIV-1 treatment and prevention, and, remarkably, achieved 100% protection in women for the first time. These findings represent a significant advancement in treatment and prevention of HIV-1 infection, offering the potential to profoundly impact the global course of the HIV epidemic.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"21 1\",\"pages\":\"\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jmedchem.5c01625\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.5c01625","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

摘要

HIV衣壳对病毒生命周期至关重要，使其成为治疗干预的一个有希望的目标。2006年，研究人员开展了一项筛选活动，以确定能够破坏蛋白质-蛋白质相互作用的小分子，这些小分子是形成37mda富勒烯锥形衣壳的1500个衣壳单体自组装所必需的。多年来进行了许多化合物设计周期，以发现共同提供多阶段HIV衣壳抑制剂lenacapavir的复杂结构元件。Lenacapavir是迄今为止最有效（HIV-1 EC50 = 105 pM）和作用时间最长的HIV抗病毒药物，具有独特的每年两次给药方案。在临床上，lenacapavir已显示出治疗和预防HIV-1的强大功效，并且值得注意的是，首次在妇女中实现了100%的保护。这些发现表明，在治疗和预防艾滋病毒-1感染方面取得了重大进展，有可能对艾滋病毒流行的全球进程产生深远影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Discovery of Lenacapavir: First-in-Class Twice-Yearly Capsid Inhibitor for HIV-1 Treatment and Pre-exposure Prophylaxis.

The HIV capsid is essential to the virus lifecycle, making it a promising target for therapeutic intervention. In 2006, a screening campaign was initiated to identify small molecules capable of disrupting the protein-protein interactions required for self-assembly of the 1500 capsid monomers that form the 37 MDa fullerene cone-shaped capsid. Numerous compound design cycles over many years were undertaken to discover the complex structural elements that together afford the multistage HIV capsid inhibitor lenacapavir. Lenacapavir is the most potent (HIV-1 EC50 = 105 pM) and longest-acting HIV antiviral to date, with a unique twice-yearly dosing regimen. Clinically, lenacapavir has demonstrated robust efficacy for both HIV-1 treatment and prevention, and, remarkably, achieved 100% protection in women for the first time. These findings represent a significant advancement in treatment and prevention of HIV-1 infection, offering the potential to profoundly impact the global course of the HIV epidemic.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.