2. Academic Validation
  3. Design and biological evaluation of novel HIV-1 protease inhibitors with isopropanol as P1' ligand to enhance binding with S1' subsite

Design and biological evaluation of novel HIV-1 protease inhibitors with isopropanol as P1' ligand to enhance binding with S1' subsite

  • Bioorg Med Chem. 2020 Aug 15;28(16):115623. doi: 10.1016/j.bmc.2020.115623.
Mei Zhu 1,  Ling Ma 1,  Biao Dong 1,  Guoning Zhang 1,  Juxian Wang 1,  Jinming Zhou 2,  Shan Cen 3,  Yucheng Wang 4
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
  • 2 Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua 321004, China. Electronic address: zhoujinming@zjnu.edu.cn.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. Electronic address: shancen@imb.pumc.edu.cn.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. Electronic address: wangyucheng@imb.pumc.edu.cn.
PMID: 32690263 DOI: 10.1016/j.bmc.2020.115623
Abstract

Newly designed HIV-1 Protease Inhibitors that maximize interactions with the protein backbone, especially in the form of hydrogen bonds, may enhance the Antiviral potency of these compounds and minimize acquisition of drug-resistant mutations. Herein, we described a series of new HIV-1 PIs containing Phenols as the P2 ligands and chiral isopropanol as the P1' ligands, in combination with 4-trifluoromethylphenylsulfonamide or 4-nitrophenylsulfonamide as the P2' ligands. And most of these compounds exhibited nanomolar inhibitory potency. In particular, inhibitors 13c and 13e with 4-trifluoromethylphenylsulfonamide as the P2' ligand and (R) - isopropanol as the P1' ligand, exhibited Antiviral IC50 values of 1.64 nM and 2.33 nM, respectively. Furthermore, they also showed remarkable activity against wild-type and DRV-resistant HIV-1 variants that raised the prospect of designing more effective PIs further.

Keywords

Isopropanol; P1′ ligands; P2 ligands; Phenols; anti-HIV-1 protease activity.

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