Synthesis, enantiomeric resolution and biological evaluation of HIV capsid inhibition activity for racemic, (S)- and (R)-PF74

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:Memarzadeh, Ms Sarah and Wilson, Professor Sam and France, Dr David and Hellam, Miss Lorna and Ruddell, Mr Stuart and Sugrue, Dr Elena
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 > Institute of Infection Immunity and Inflammation
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190490Engineering and Physical Sciences Doctoral Training Grant 2012-16Mary Beth KneafseyEngineering and Physical Sciences Research Council (EPSRC)EP/K503058/1Research and Innovation Services
305200DTP 2018-19 University of GlasgowMary Beth KneafseyEngineering and Physical Sciences Research Council (EPSRC)EP/R513222/1MVLS - Graduate School
311006Protein Degradation as an Anti-viral StrategyDavid FranceEngineering and Physical Sciences Research Council (EPSRC)EP/V008404/1III - Centre for Virus Research