2022-03-17 コロンビア大学
エキソヌクレアーゼは、組み立てられたRNAを「校正」し、ヌクレオシドアナログを含む新しく形成された鎖を拒絶するように効果的に働く。このような阻害剤は、COVID-19の治療において限られた価値しか持たない可能性があるというこ。実際、入院中のCOVID-19患者を対象としたSolidarity試験で、ヌクレオシドアナログのレムデシビルの効果が限定的だったのは、このためと思われる。
また、C型肝炎の治療薬であるダクラタスビルの単独投与またはソホスブビルとの併用投与が、COVID-19の治療に有用である可能性を示している研究もある。
<関連情報>
- https://hospitalhealthcare.com/covid-19/exonuclease-and-polymerase-inhibitor-combination-a-potential-therapeutic-target-for-covid-19/
- https://pubmed.ncbi.nlm.nih.gov/35194144/
抗ウイルス剤の併用によりSARS-CoV-2ポリメラーゼとエキソヌクレアーゼを阻害し、ウイルス細胞培養でCOVID-19の治療効果を実証する。 Combination of antiviral drugs inhibits SARS-CoV-2 polymerase and exonuclease and demonstrates COVID-19 therapeutic potential in viral cell culture
Free article
Abstract
SARS-CoV-2 has an exonuclease-based proofreader, which removes nucleotide inhibitors such as Remdesivir that are incorporated into the viral RNA during replication, reducing the efficacy of these drugs for treating COVID-19. Combinations of inhibitors of both the viral RNA-dependent RNA polymerase and the exonuclease could overcome this deficiency. Here we report the identification of hepatitis C virus NS5A inhibitors Pibrentasvir and Ombitasvir as SARS-CoV-2 exonuclease inhibitors. In the presence of Pibrentasvir, RNAs terminated with the active forms of the prodrugs Sofosbuvir, Remdesivir, Favipiravir, Molnupiravir and AT-527 were largely protected from excision by the exonuclease, while in the absence of Pibrentasvir, there was rapid excision. Due to its unique structure, Tenofovir-terminated RNA was highly resistant to exonuclease excision even in the absence of Pibrentasvir. Viral cell culture studies also demonstrate significant synergy using this combination strategy. This study supports the use of combination drugs that inhibit both the SARS-CoV-2 polymerase and exonuclease for effective COVID-19 treatment.
© 2022. The Author(s).
