Ruddell, S., Sugrue, E. , Memarzadeh, S., Hellam, L. M., Wilson, S. and France, D. (2021) Synthesis, enantiomeric resolution and biological evaluation of HIV capsid inhibition activity for racemic, (S)- and (R)-PF74. Molecules, 26(13), 3919. (doi: 10.3390/molecules26133919) (PMID:34206893) (PMCID:PMC8272108)
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Abstract
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 (ΔG = −73.8 kcal/mol) was calculated to be more favourable than the conformation adopted by the less active (R)-enantiomer (ΔG = −55.8 kcal/mol) in agreement with experimental observations.
| Item Type: | Articles |
|---|---|
| Additional Information: | Financial support from the EPSRC (EP/K503058/1 to S.R., EP/R513222/1 to L.M.H. and EP/V008404/1 to S.J.W. and D.J.F.) and University of Glasgow is gratefully acknowledged. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Sugrue, Dr Elena and Hellam, Miss Lorna and France, Dr David and Memarzadeh, Ms Sarah and Ruddell, Mr Stuart and Wilson, Professor Sam |
| Creator Roles: | Ruddell, S.Conceptualization, Data curation, Investigation, Writing – original draft Sugrue, E.Conceptualization, Data curation, Investigation, Writing – original draft Memarzadeh, S.Data curation, Investigation, Writing – original draft Hellam, L.Data curation, Investigation, Writing – original draft Wilson, S.Conceptualization, Funding acquisition, Resources, Writing – original draft France, D.Conceptualization, Funding acquisition, Resources, Writing – original draft |
| Authors: | Ruddell, S., Sugrue, E., Memarzadeh, S., Hellam, L. M., Wilson, S., and France, D. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research College of Science and Engineering > School of Chemistry |
| Journal Name: | Molecules |
| Publisher: | MDPI |
| ISSN: | 1420-3049 |
| ISSN (Online): | 1420-3049 |
| Published Online: | 26 June 2021 |
| Copyright Holders: | Copyright © 2021 The Authors |
| First Published: | First published in Molecules 26(13): 3919 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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