Design, Synthesis and Characterization of HIV-1 CA-Targeting Small Molecules: Conformational Restriction of PF74

Rajkumar Lalji Sahani, Raquel Diana-Rivero, Sanjeev Kumar V Vernekar, Lei Wang, Haijuan Du, Huanchun Zhang, Andres Emanuelli Castaner, Mary C. Casey, Karen A. Kirby, Philip R. Tedbury, Jiashu Xie, Stefan G. Sarafianos, Zhengqiang (ZQ) Wang

Research output: Contribution to journalArticlepeer-review


Small molecules targeting the PF74 binding site of the HIV-1 capsid protein (CA) confer potent and mechanistically unique antiviral activities. Structural modifications of PF74 could further the understanding of ligand binding modes, diversify ligand chemical classes, and allow identification of new variants with balanced antiviral activity and metabolic stability. In the current work, we designed and synthesized three series of PF74-like analogs featuring conformational constraints at the aniline terminus or the phenylalanine carboxamide moiety, and characterized them using a biophysical thermal shift assay (TSA), cell-based antiviral and cytotoxicity assays, and in vitro metabolic stability assays in human and mouse liver microsomes. These studies showed that the two series with the phenylalanine carboxamide moiety replaced by a pyridine or imidazole ring can provide viable hits. Subsequent SAR identified an improved analog 15 which effectively inhibited HIV-1 (EC50 = 0.31 μM), strongly stabilized CA hexamer (ΔTm = 8.7 °C), and exhibited substantially enhanced metabolic stability (t1/2 = 27 min for 15 vs. 0.7 min for PF74). Metabolic profiles from the microsomal stability assay also indicate that blocking the C5 position of the indole ring could lead to increased resistance to oxidative metabolism.

Original languageEnglish (US)
Issue number3
StatePublished - Mar 15 2021


  • capsid protein
  • conformational constraint
  • HIV-1
  • metabolic stability
  • PF74

PubMed: MeSH publication types

  • Journal Article

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