Tripeptide analogues of MG132 as protease inhibitors

Ashok D Pehere; Steven Nguyen; Sarah K Garlick; Danny W Wilson; Irene Hudson; Matthew J Sykes; James D Morton; Andrew D Abell

doi:10.1016/j.bmc.2018.12.022

Tripeptide analogues of MG132 as protease inhibitors

Bioorg Med Chem. 2019 Jan 15;27(2):436-441. doi: 10.1016/j.bmc.2018.12.022. Epub 2018 Dec 14.

Authors

Ashok D Pehere¹, Steven Nguyen², Sarah K Garlick³, Danny W Wilson⁴, Irene Hudson⁵, Matthew J Sykes², James D Morton³, Andrew D Abell⁶

Affiliations

¹ Department of Chemistry, and Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, South Australia 5005, Australia. Electronic address: adpehere@mdanderson.org.
² Centre for Cancer Diagnostics and Therapeutics, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia.
³ Wine, Food & Molecular Biosciences, Lincoln University, Faculty of Agriculture and Life Sciences, PO Box 85084, Canterbury 7647, New Zealand.
⁴ Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide 5005, Australia; Burnet Institute, 85 Commercial Road, Melbourne 3004, Victoria, Australia.
⁵ Department of Statistics, Data Science & Epidemiology, Swinburne University of Technology, Hawthorn, VIC 3122, Australia.
⁶ Department of Chemistry, and Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, South Australia 5005, Australia.

PMID: 30581047
DOI: 10.1016/j.bmc.2018.12.022

Abstract

The 26S proteasome and calpain are linked to a number of important human diseases. Here, we report a series of analogues of the prototypical tripeptide aldehyde inhibitor MG132 that show a unique combination of high activity and selectivity for calpains over proteasome. Tripeptide aldehydes (1-3) with an aromatic P3 substituent show enhanced activity and selectivity against ovine calpain 2 relative to chymotrypsin-like activity of proteasome. Docking studies reveal the key contacts between inhibitors and calpain to confirm the importance of the S3 pocket with respect to selectivity between calpains 1 and 2 and the proteasome.

Keywords: 26S proteasome inhibitors; Calpain inhibitors; Medicinal chemistry; Peptidomimetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimalarials / chemical synthesis
Antimalarials / chemistry
Antimalarials / pharmacology
Calpain / chemistry
Catalytic Domain
Cysteine Proteinase Inhibitors / chemical synthesis
Cysteine Proteinase Inhibitors / chemistry
Cysteine Proteinase Inhibitors / pharmacology*
Leupeptins / chemical synthesis
Leupeptins / chemistry
Leupeptins / pharmacology*
Molecular Docking Simulation
Molecular Structure
Plasmodium falciparum / enzymology
Proteasome Endopeptidase Complex / chemistry
Proteasome Inhibitors / chemical synthesis
Proteasome Inhibitors / chemistry
Proteasome Inhibitors / pharmacology*
Protein Conformation
Rats
Sheep
Swine

Substances

Antimalarials
Cysteine Proteinase Inhibitors
Leupeptins
Proteasome Inhibitors
Calpain
Proteasome Endopeptidase Complex
ATP dependent 26S protease
benzyloxycarbonylleucyl-leucyl-leucine aldehyde