2. Academic Validation
  3. Preliminary SAR and biological evaluation of potent HIV-1 protease inhibitors with pyrimidine bases as novel P2 ligands to enhance activity against DRV-resistant HIV-1 variants

Preliminary SAR and biological evaluation of potent HIV-1 protease inhibitors with pyrimidine bases as novel P2 ligands to enhance activity against DRV-resistant HIV-1 variants

  • Eur J Med Chem. 2020 Jan 1;185:111866. doi: 10.1016/j.ejmech.2019.111866.
Mei Zhu 1,  Ling Ma 1,  Huiyu Zhou 1,  Biao Dong 1,  Yujia Wang 1,  Zhen Wang 2,  Jinming Zhou 1,  Guoning Zhang 1,  Juxian Wang 1,  Chen Liang 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 Lady Davis Institute for Medical Research and McGill AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: shancen@hotmail.com.
  • 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: 31734023 DOI: 10.1016/j.ejmech.2019.111866
Abstract

Introducing pyrimidine Bases, the basic components of nucleic acid, to P2 ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) Protease Inhibitors because of the carbonyl and amino groups promoting the formation of extensive hydrogen bonding interactions. In this work, we provide evidence that inhibitor 10e, with N-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide as the P2 ligand and a 4-methoxylphenylsulfonamide as the P2' ligand, displayed remarkable Enzyme inhibitory and Antiviral activity, with the IC50 2.53 nM in vitro and a promising inhibition ratio with 68% against wild-type HIV-1 in vivo, with low cytotoxicity. This inhibitor also exhibited appreciable Antiviral activity against DRV-resistant HIV-1 variants, which was of great value for further study.

Keywords

Antiviral activity; DRV-Resistant HIV-1 variants; HIV-1 protease inhibitors; Pyrimidine bases.

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