2. Academic Validation
  3. Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-one Scaffold as Potent HIV Capsid Modulators

Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-one Scaffold as Potent HIV Capsid Modulators

  • J Med Chem. 2023 Dec 14;66(23):16303-16329. doi: 10.1021/acs.jmedchem.3c01647.
Shujing Xu 1,  Lin Sun 1,  Michael Barnett 2,  Xujie Zhang 1,  Dang Ding 1,  Anushka Gattu 3,  Dazhou Shi 1,  Jamie R H Taka 2,  Wenli Shen 1,  Xiangyi Jiang 1,  Simon Cocklin 4,  Erik De Clercq 5,  Christophe Pannecouque 5,  David C Goldstone 2,  Xinyong Liu 1,  Alexej Dick 3,  Peng Zhan 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
  • 2 School of Biological Sciences, The University of Auckland, 3A Symonds St, Auckland 1010, New Zealand.
  • 3 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, United States.
  • 4 Specifica Inc., The Santa Fe Railyard, 1607 Alcaldesa Street, Santa Fe, New Mexico 87501, United States.
  • 5 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
PMID: 38054267 DOI: 10.1021/acs.jmedchem.3c01647
Abstract

Optimization of compound 11L led to the identification of novel HIV capsid modulators, quinazolin-4-one-bearing phenylalanine derivatives, displaying potent Antiviral activities against both HIV-1 and HIV-2. Notably, derivatives 12a2 and 21a2 showed significant improvements, with 2.5-fold over 11L and 7.3-fold over PF74 for HIV-1, and approximately 40-fold over PF74 for HIV-2. The X-ray co-crystal structures confirmed the multiple pocket occupation of 12a2 and 21a2 in the binding site. Mechanistic studies revealed a dual-stage inhibition profile, where the compounds disrupted capsid-host factor interactions at the early stage and promoted capsid misassembly at the late stage. Remarkably, 12a2 and 21a2 significantly promoted capsid misassembly, outperforming 11L, PF74, and LEN. The substitution of easily metabolized amide bond with quinolin-4-one marginally enhanced the stability of 12a2 in human liver microsomes compared to controls. Overall, 12a2 and 21a2 highlight their potential as potent HIV capsid modulators, paving the way for future advancements in anti-HIV drug design.

Figures
Products