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

Xu, Shujing; Sun, Lin; Barnett, Michael; Zhang, Xujie; Ding, Dang; Gattu, Anushka; Shi, Dazhou; Taka, Jamie R. H.; Shen, Wenli; Jiang, Xiangyi; Cocklin, Simon; De Clercq, Erik; Pannecouque, Christophe; Goldstone, David C.; Liu, Xinyong; Dick, Alexej; Zhan, Peng

doi:10.1021/acs.jmedchem.3c01647

Cited by 2 publications

(1 citation statement)

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“…Despite its potent and mechanistically interesting antiviral phenotypes, PF74 is not a viable antiviral lead due to the prohibitively low metabolic stability [19]. We have chemically profiled PF74 extensively with the synthesis of a large number of analogs [20], and along with others, have explored different PF74 subtypes for enhanced metabolic stability [6,19,[21][22][23][24][25][26][27][28][29][30][31][32]. GS-6207 (lenacapavir), on the other hand, is extraordinarily stable toward oxidative metabolism, presumably owing to its high fluorine content (Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of New GS-6207 Subtypes for Targeting HIV-1 Capsid Protein

Akther,

McFadden,

Zhang

et al. 2024

IJMS

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HIV-1 capsid protein (CA) is the molecular target of the recently FDA-approved long acting injectable (LAI) drug lenacapavir (GS-6207). The quick emergence of CA mutations resistant to GS-6207 necessitates the design and synthesis of novel sub-chemotypes. We have conducted the structure-based design of two new sub-chemotypes combining the scaffold of GS-6207 and the N-terminal cap of PF74 analogs, the other important CA-targeting chemotype. The design was validated via induced-fit molecular docking. More importantly, we have worked out a general synthetic route to allow the modular synthesis of novel GS-6207 subtypes. Significantly, the desired stereochemistry of the skeleton C2 was confirmed via an X-ray crystal structure of the key synthetic intermediate 22a. Although the newly synthesized analogs did not show significant potency, our efforts herein will facilitate the future design and synthesis of novel subtypes with improved potency.

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