病毒学
蛋白酶抑制剂(药理学)
药理学
蛋白酶
博赛泼维
抗药性
生物
酶
丙型肝炎病毒
病毒
微生物学
病毒载量
生物化学
利巴韦林
抗逆转录病毒疗法
作者
Michael Westberg,Yichi Su,Xinzhi Zou,Pinghan Huang,Arjun Rustagi,Jaishree Garhyan,Parag R. Patel,Daniel Fernández,Yan Wu,Dongmei Zhao,Chieh‐Wen Lo,Marwah Karim,Lin Ning,Aimee Beck,Panatda Saenkham-Huntsinger,Vivian Tat,Aleksandra Drelich,Bi‐Hung Peng,Shirit Einav,Chien‐Te K. Tseng,Catherine A. Blish,Michael Z. Lin
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2024-03-13
卷期号:16 (738)
被引量:5
标识
DOI:10.1126/scitranslmed.adi0979
摘要
Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 M pro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.
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