Design, synthesis, and mechanistic study of 2-piperazineone-bearing peptidomimetics as novel HIV capsid modulators

Abstract

We report the design, synthesis, and mechanistic study of a novel series of 2-piperazineone peptidomimetics as HIV capsid modulators by mimicking the structure of host factors binding to CA.

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

“…This facilitates hydrogen bond interactions between Lys70/Arg70 and the carbonyl group on the piperazinone or the carbonyl group on the amide bond, which could explain why these two scaffolds display high anti-HIV-1 and anti-HIV-2 activity. However, arginine is more basic and has more polar hydrogens than lysine, resulting in a stronger hydrogen bond formation profile, resulting in these compounds prefer suppressing HIV-2 over HIV-1. While scaffolds II and VII , also contained the piperazinone structure, the sulfonyl group replaced by the acyl group might disrupt the active conformation of the compounds, leading to a significant reduction of their anti-HIV activity. The anti-HIV-2 activities of scaffold III were significantly superior to their anti-HIV-1 activities, making them selective HIV-2 CA modulators. This might be attributed to the fact that the benzene ring can simultaneously form cation-π interactions with Arg70 and Arg173, thereby exhibiting better anti-HIV-2 activity.…”

“…(A) Binding site of HIV-1 CA hexamer (PDB code: 4XFZ). (B) Binding site of HIV-2 CA hexamer model (obtained by homology modeling). The figures were generated in PyMOL ().…”

“…We also aimed to tackle a key drawback associated with metabolic instability. Employing computational methods ,,, and subsequent experimental validations, we assessed the metabolic stability of 12a2 and 21a2 in human liver microsomes and plasma. The moderate stability displayed by these compounds provides a valuable starting point for further PK optimization.…”

“…When R 2 = H or F, R 3 = OCH 3 , R 4 = NH 2 , the antiviral activity of the analogs with SO 2 CH 3 at R 1 decreased in comparison with unsubstituted and F-or Cl-substituted R 3A,B). 33 Herein, we have analyzed recent results to develop a deeper insight into the SARs of anti-HIV potency and the structure−selectivity relationships (SERs) of anti-HIV-1/HIV-2 potency (Figure 3C, Tables S1−S8).…”

“…We employed both the monomeric and hexameric forms of CA in these experiments, utilizing a previously established protocol. 33 PF74 and 11L were used as controls. Table 2 and Figures 4 and 5 show that both compounds directly bound with CA's monomeric and hexameric forms.…”