P1 Glutamine isosteres in the design of inhibitors of 3C/3CL protease of human viruses of the Pisoniviricetes class

Louise A Stubbing; Jonathan G Hubert; Joseph Bell-Tyrer; Yann O Hermant; Sung Hyun Yang; Alice M McSweeney; Geena M McKenzie-Goldsmith; Vernon K Ward; Daniel P Furkert; Margaret A Brimble

doi:10.1039/d3cb00075c

P₁ Glutamine isosteres in the design of inhibitors of 3C/3CL protease of human viruses of the Pisoniviricetes class

RSC Chem Biol. 2023 Jun 21;4(8):533-547. doi: 10.1039/d3cb00075c. eCollection 2023 Aug 3.

Authors

Louise A Stubbing^{1

2}, Jonathan G Hubert¹, Joseph Bell-Tyrer¹, Yann O Hermant^{1

2}, Sung Hyun Yang¹, Alice M McSweeney^{2

3}, Geena M McKenzie-Goldsmith^{2

3}, Vernon K Ward^{2

3}, Daniel P Furkert^{1

2}, Margaret A Brimble^{1

2}

Affiliations

¹ School of Chemical Sciences, The University of Auckland 23 Symonds Street and 3b Symonds Street Auckland 1142 New Zealand m.brimble@auckland.ac.nz.
² Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland 3b Symonds Street Auckland 1142 New Zealand.
³ Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago PO Box 56, 720 Cumberland Street Dunedin 9054 New Zealand.

Abstract

Viral infections are one of the leading causes of acute morbidity in humans and much endeavour has been made by the synthetic community for the development of drugs to treat associated diseases. Peptide-based enzyme inhibitors, usually short sequences of three or four residues, are one of the classes of compounds currently under development for enhancement of their activity and pharmaceutical properties. This review reports the advances made in the design of inhibitors targeting the family of highly conserved viral proteases 3C/3CL^pro, which play a key role in viral replication and present minimal homology with mammalian proteases. Particular focus is put on the reported development of P₁ glutamine isosteres to generate potent inhibitors mimicking the natural substrate sequence at the site of recognition.'

Publication types

Review