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Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assaysстатья
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 4 марта 2022 г.
- Авторы: Curreli Francesca, Ahmed Shahad, Victor Sofia M.B., Drelich Aleksandra, Panda Siva S., Altieri Andrea, Kurkin Alexander V., Tseng Chien-Te K., Hillyer Christopher D., Debnath Asim K.
- Журнал: Viruses
- Том: 14
- Номер: 1
- Год издания: 2022
- Издательство: MDPI
- Местоположение издательства: Basel, Switzerland
- Первая страница: 69
- DOI: 10.3390/v14010069
- Аннотация: We report the discovery of several highly potent small molecules with low-nM potencyagainst severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC50: 13 nM), SARS-CoV-2 (IC50: 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC50: 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC100) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 M. The most active inhibitors also potently inhibited variants of concern (VOCs), including the UK (B.1.1.7) and South African (B.1.351) variants and the Delta variant (B.1.617.2) originally identified in India in pseudovirus-based assay. Surface plasmon resonance (SPR)analysis with one potent inhibitor confirmed that it binds to the prefusion SARS-CoV-2 spike proteintrimer. These small-molecule inhibitors prevented virus-mediated cell–cell fusion. The absorption,distribution, metabolism, and excretion (ADME) data for one of the most active inhibitors, NBCoV1, demonstrated drug-like properties. An in vivo pharmacokinetics (PK) study of NBCoV1 in ratsdemonstrated an excellent half-life (t1/2) of 11.3 h, a mean resident time (MRT) of 14.2 h, and oralbioavailability. We expect these lead inhibitors to facilitate the further development of preclinical and clinical candidates.
- Добавил в систему: Куркин Александр Витальевич