Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage

European Journal of Medicinal Chemistry
Xin ZhangDan-Qing Song

Abstract

Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivatives were synthesized and evaluated for their anti-filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) analysis indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compound 2e exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo. It also displayed a good pharmacokinetic and safety profile in vivo, indicating an ideal druglike feature. The primary mechanism study showed that 2e could block a late stage of viral entry, mainly through inhibiting cysteine cathepsin B activity of host components. We consider compound 2e to be a promising broad-spectrum anti-filovirus agent with the advantages of a unique chemical scaffold and a specific biological mechanism.

Citations

Mar 22, 2019·Viruses·Cristiano SalataGiorgio Palù
Nov 17, 2019·International Journal of Molecular Sciences·Hui-I YuYing-Ray Lee
Oct 30, 2020·OncoTargets and Therapy·Lijun ZhangWei Hu
Oct 31, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kun WangDanqing Song
Apr 20, 2019·Current Opinion in Virology·Megan R Edwards, Christopher F Basler
Dec 23, 2020·Journal of Natural Products·Mitchell P ChristyWilliam H Gerwick

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