1352879-65-2Relevant articles and documents
Synthesis, enantiomeric resolution and biological evaluation of hiv capsid inhibition activity for racemic, (S)-and (r)-pf74
France, David J.,Hellam, Lorna Mae,Memarzadeh, Sarah,Ruddell, Stuart,Sugrue, Elena,Wilson, Sam J.
, (2021)
PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack of information regarding the optical purity (enantiomeric excess) of the single stereogenic centre of PF74 has resulted in ambiguity as to the potency of different samples of this compound. Herein is described the synthesis of enantiomerically enriched (S)-and (R)-PF74 and further enrichment of the samples (≥98%) using chiral HPLC resolution. The biological activities of each enantiomer were then evaluated, which determined (S)-PF74 (IC50 1.5 μM) to be significantly more active than (R)-PF74 (IC50 19 μM). Computational docking studies were then conducted to rationalise this large discrepancy in activity, which indicated different binding conformations for each enantiomer. The binding energy of the conformation adopted by the more active (S)-PF74 (?G = ?73.8 kcal/mol) was calculated to be more favourable than the conformation adopted by the less active (R)-enantiomer (?G = ?55.8 kcal/mol) in agreement with experimental observations.
Novel HIV-1 capsid-targeting small molecules of the PF74 binding site
Casey, Mary C.,Du, Haijuan,Hachiya, Atsuko,Kankanala, Jayakanth,Kirby, Karen A.,Sahani, Rajkumar Lalji,Sarafianos, Stefan G.,Tedbury, Philip R.,Vernekar, Sanjeev Kumar V.,Wang, Lei,Wang, Zhengqiang,Xie, Jiashu,Zhang, Huanchun
, (2020/08/19)
The PF74 binding site in HIV-1 capsid protein (CA) is a compelling antiviral drug target. Although PF74 confers mechanistically distinct antiviral phenotypes by competing against host factors for CA binding, it suffers from prohibitively low metabolic sta
Microplate-based assay for identifying small molecules that bind a specific intersubunit interface within the assembled HIV-1 capsid
Halambage, Upul D.,Wong, Jason P.,Melancon, Bruce J.,Lindsley, Craig W.,Aiken, Christopher
supporting information, p. 5190 - 5195 (2015/09/15)
Despite the availability of>30 effective drugs for managing HIV-1 infection, no current therapy is curative, and long-term management is challenging owing to the emergence and spread of drug-resistant mutants. Identification of drugs against novel HIV-1 targets would expand the current treatment options and help to control resistance. The highly conserved HIV-1 capsid protein represents an attractive target because of its multiple roles in replication of the virus. However, the low antiviral potencies of the reported HIV-1 capsid-targeting inhibitors render them unattractive for therapeutic development. To facilitate the identification of more-potent HIV-1 capsid inhibitors, we developed a scintillation proximity assay to screen for small molecules that target a biologically active and specific intersubunit interface in the HIV-1 capsid. The assay, which is based on competitive displacement of a known capsid-binding small-molecule inhibitor, exhibited a signal-to-noise ratio of>9 and a Z factor of>0.8. In a pilot screen of a chemical library containing 2,400 druglike compounds, we obtained a hit rate of 1.8%. This assay has properties that are suitable for screening large compound libraries to identify novel HIV-1 capsid ligands with antiviral activity.
