Novel HIV-1 capsid-targeting small molecules of the PF74 binding site.
Novel HIV-1 capsid-targeting small molecules of the PF74 binding site.
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DOI：
10.1016/j.ejmech.2020.112626
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发表时间：
2020-10-15
影响因子：
6.7
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Wang L;Casey MC;Vernekar SKV;Sahani RL;Kankanala J;Kirby KA;Du H;Hachiya A;Zhang H;Tedbury PR;Xie J;Sarafianos SG;Wang Z
The PF74 binding site in HIV-1 capsid protein (CA) is a compelling antiviral drug target. Although PF74 confers mechanistically distinct antiviral phenotypes by competing against host factors for CA binding, it suffers from prohibitively low metabolic stability. Therefore, there has been increasing interest in designing novel sub-chemotypes of PF74 with similar binding mode and improved metabolic stability. We report herein our efforts to explore the inter-domain interacting indole moiety for designing novel CA-targeting small molecules. Our design includes simple substitution on the indole ring, and more importantly, novel sub-chemotypes with the indole moiety replaced with a few less electron-rich rings. All 56 novel analogs were synthesized and evaluated for antiviral activity, cytotoxicity, and impact on CA hexamer stability. Selected analogs were tested for metabolic stability in liver microsomes. Molecular modeling was performed to verify compound binding to the PF74 site. In the end, 5-hydroxyindole analogs (8,9 and 12) showed improved potency (up to 20-fold) over PF74. Of the novel sub-chemotypes, α- and β-naphthyl analogs (33 and 27) exhibited sub micromolar antiviral potencies comparable to that of PF74. Interestingly, although only moderately inhibiting HIV-1 (single-digit micromolar EC50s), analogs of the 2-indolone sub-chemotype consistently lowered the melting point (Tm) of CA hexamers, some with improved metabolic stability over PF74.
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DOI：
10.1038/nrmicro3503
发表时间：
2015-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Campbell EM;Hope TJ
通讯作者：
Hope TJ
影响因子：
5.4
作者：
Buffone, Cindy;Martinez-Lopez, Alicia;Diaz-Griffero, Felipe
通讯作者：
Diaz-Griffero, Felipe
影响因子：
5
作者：
Le Sage, Valerie;Mouland, Andrew J.;Valiente-Echeverria, Fernando
通讯作者：
Valiente-Echeverria, Fernando
影响因子：
7.7
作者：
Bejarano, David Alejandro;Peng, Ke;Kraeusslich, Hans-Georg
通讯作者：
Kraeusslich, Hans-Georg
影响因子：
6.7
作者：
Blair WS;Pickford C;Irving SL;Brown DG;Anderson M;Bazin R;Cao J;Ciaramella G;Isaacson J;Jackson L;Hunt R;Kjerrstrom A;Nieman JA;Patick AK;Perros M;Scott AD;Whitby K;Wu H;Butler SL
通讯作者：
Butler SL