Conformationally Controlled sp3‐Hydrocarbon‐Based α‐Helix Mimetics

Lydia I. Dewis, Rudrakshula Madhavachary, Christopher Williams, Elisabetta Chiarparin, Eddie L. Myers, Craig P. Butts, Varinder Kumar Aggarwal

Research output: Contribution to journalArticle (Academic Journal)peer-review

1 Citation (Scopus)

Abstract

With over 60% of protein–protein interfaces featuring an α-helix, α-helix mimetics as inhibitors of these biomolecular interactions is a prevalent therapeutic strategy. However, methods to control the conformation of mimetics, thus enabling maximum efficacy, such as backbone stapling, can be restrictive. Alternatively, conformation can be controlled through the introduction of destabilizing interactions, such as the syn-pentane interaction. This tactic, which is often adopted by Nature, is not a common feature of lead optimization, presumably owing to the significant synthetic effort required. Through assembly-line synthesis with NMR and computational analysis, we have designed, prepared and characterized alternating syn–anti configured contiguously substituted hydrocarbons, which, through the avoidance of syn-pentane interactions, adopt well-defined conformations that present functional groups in an arrangement that mimics the α-helix. The design of a p53 mimetic, which binds to Mdm2 with moderate to good affinity, demonstrates the therapeutic promise of these scaffolds.
Original languageEnglish
Article numbere202301209
JournalAngewandte Chemie - International Edition
Volume62
Issue number23
Early online date5 Apr 2023
DOIs
Publication statusPublished - 24 May 2023

Bibliographical note

Funding Information:
L.I.D. thanks the EPSRC Bristol Chemical Synthesis Doctoral Training Centre and AstraZeneca for studentship support (EP/G036764/1) and the BrisSynBio for equipment funding (BB/L01386X/1). R.M. thanks the EU for an H2020 Marie Skłodowska‐Curie Fellowship (Grant 794053). The authors thank the following UoB personnel: Prof. A. Mulholland, Prof. D. Woolfson and Prof. M. Crump for helpful discussions, Dr. J. Pradeilles for lithiation‐borylation advice, Dr. S. Zhong for NMR conformational analysis advice and Dr. C. Dickson for MATLAB scripts to assist in NMR Boltzmann averaging.

Funding Information:
L.I.D. thanks the EPSRC Bristol Chemical Synthesis Doctoral Training Centre and AstraZeneca for studentship support (EP/G036764/1) and the BrisSynBio for equipment funding (BB/L01386X/1). R.M. thanks the EU for an H2020 Marie Skłodowska-Curie Fellowship (Grant 794053). The authors thank the following UoB personnel: Prof. A. Mulholland, Prof. D. Woolfson and Prof. M. Crump for helpful discussions, Dr. J. Pradeilles for lithiation-borylation advice, Dr. S. Zhong for NMR conformational analysis advice and Dr. C. Dickson for MATLAB scripts to assist in NMR Boltzmann averaging.

Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Structured keywords

  • BCS and TECS CDTs

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