2. Academic Validation
  3. Discovery of potent HIV-1 NNRTIs by CuAAC click-chemistry-based miniaturized synthesis, rapid screening and structure optimization

Discovery of potent HIV-1 NNRTIs by CuAAC click-chemistry-based miniaturized synthesis, rapid screening and structure optimization

  • Eur J Med Chem. 2024 Nov 5:277:116772. doi: 10.1016/j.ejmech.2024.116772.
Lanlan Jing 1,  Gaochan Wu 1,  Fabao Zhao 1,  Xiangyi Jiang 1,  Na Liu 1,  Da Feng 1,  Yanying Sun 1,  Tao Zhang 1,  Erik De Clercq 2,  Christophe Pannecouque 2,  Dongwei Kang 3,  Xinyong Liu 4,  Peng Zhan 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China.
  • 2 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Leuven, B-3000, Belgium.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China. Electronic address: kangdongwei@126.com.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China. Electronic address: xinyongl@sdu.edu.cn.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China. Electronic address: zhanpeng1982@sdu.edu.cn.
PMID: 39167895 DOI: 10.1016/j.ejmech.2024.116772
Abstract

In addressing the urgent need for novel HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) to combat drug resistance, we employed CuAAC Click Chemistry to construct a diverse 312-member diarylpyrimidine (DAPY) derivative library. This rapid synthesis approach facilitated the identification of A6N36, demonstrating exceptional HIV-1 RT inhibitory activity. Moreover, it was demonstrated with EC50 values of 1.8-8.7 nM for mutant strains L100I, K103 N, Y181C, and E138K, being equipotent or superior to that of ETR. However, A6N36's efficacy was compromised against specific resistant strains (Y188L, F227L + V106A and RES056), highlighting a need for further optimization. Through scaffold hopping, we optimized this lead to develop 10c, which exhibited broad-spectrum activity with EC50 values ranging from 3.2 to 57.5 nM and superior water solubility. Molecular docking underscored the key interactions of 10c within the NNIBP. Our findings present 10c as a promising NNRTI lead, illustrating the power of Click Chemistry and rational design in combatting HIV-1 resistance.

Keywords

CuAAC; Direct screening; HIV-1; NNIBP; NNRTIs.

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