8fiu | pdb_00008fiu
Potent long-acting inhibitors targeting HIV-1 capsid based on a versatile quinazolin-4-one scaffold
Structural highlights
FunctionGAG_HV1N5 Matrix protein p17 targets Gag and Gag-Pol polyproteins to the plasma membrane via a multipartite membrane binding signal, that includes its myristoylated N-terminus. Also mediates nuclear localization of the preintegration complex. Implicated in the release from host cell mediated by Vpu. Capsid protein p24 forms the conical core of the virus that encapsulates the genomic RNA-nucleocapsid complex. Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. p6-gag plays a role in budding of the assembled particle by interacting with the host class E VPS proteins TSG101 and PDCD6IP/AIP1 (By similarity). Publication Abstract from PubMedLong-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a >/=1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection in vitro, are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs. Potent Long-Acting Inhibitors Targeting the HIV-1 Capsid Based on a Versatile Quinazolin-4-one Scaffold.,Gillis EP, Parcella K, Bowsher M, Cook JH, Iwuagwu C, Naidu BN, Patel M, Peese K, Huang H, Valera L, Wang C, Kieltyka K, Parker DD, Simmermacher J, Arnoult E, Nolte RT, Wang L, Bender JA, Frennesson DB, Saulnier M, Wang AX, Meanwell NA, Belema M, Hanumegowda U, Jenkins S, Krystal M, Kadow JF, Cockett M, Fridell R J Med Chem. 2023 Feb 9;66(3):1941-1954. doi: 10.1021/acs.jmedchem.2c01732. Epub , 2023 Jan 31. PMID:36719971[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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