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 3 publications

(1 citation statement)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

Breaking the impossible: The evolutionary journey of lenacapavir, a long-acting anti-HIV drug

Tang,

Wei,

Zhan

2024

Chinese Chemical Letters

View full text Add to dashboard Cite

“Pseudosubstrate Envelope”/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency

Xu,

Wang,

Zhou

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

Based on our proposed "pseudosubstrate envelope" concept, 25 benzothiazole-bearing HIV capsid protein (CA) modulators were designed and synthesized under the guidance of free energy perturbation technology. The most potent compound, IC-1k, exhibited an EC 50 of 2.69 nM against HIV-1, being 393 times more potent than the positive control PF74. Notably, IC-1k emerged as the highest ligand efficiency (LE = 0.32) HIV CA modulator, surpassing that of the approved drug lenacapavir (LE = 0.21). Surface plasmon resonance assay and crystallographic analysis confirmed that IC-1k targeted HIV-1 CA within the chemical space of the "pseudosubstrate envelope". Further mechanistic studies revealed a dual-stage inhibition profile: IC-1k disrupted earlystage capsid−host-factor interactions and promoted late-stage capsid misassembly. Preliminary pharmacokinetic evaluations demonstrated significantly improved metabolic stability in human liver microsomes for IC-1k (T 1/2 = 91.3 min) compared to PF74 (T 1/2 = 0.7 min), alongside a favorable safety profile. Overall, IC-1k presents a promising lead compound for further optimization.

show abstract

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

Cited by 3 publications

References 47 publications

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

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

Breaking the impossible: The evolutionary journey of lenacapavir, a long-acting anti-HIV drug

“Pseudosubstrate Envelope”/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency

Contact Info

Product

Resources

About