Investigating the phosphinic acid tripeptide mimetic DG013A as a tool compound inhibitor of the M1-aminopeptidase ERAP1.

Aminopeptidases / antagonists & inhibitors Dose-Response Relationship, Drug Enzyme Inhibitors / chemical synthesis Humans Minor Histocompatibility Antigens / metabolism Models, Molecular Molecular Structure Oligopeptides / chemical synthesis Phosphinic Acids / chemical synthesis Structure-Activity Relationship

Chemical probe DG013A ERAP1 M1-aminopeptidase Permeability

Journal

Bioorganic & medicinal chemistry letters

ISSN: 1464-3405

Titre abrégé: Bioorg Med Chem Lett

Pays: England

ID NLM: 9107377

Informations de publication

Date de publication:
15 06 2021

Historique:

received: 19 02 2021

revised: 26 03 2021

accepted: 13 04 2021

pubmed: 23 4 2021

medline: 3 11 2021

entrez: 22 4 2021

Statut: ppublish

Résumé

ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation of the highly polymorphic ERAP1 has been implicated in autoimmune disease and cancer. To test this hypothesis and establish the role of ERAP1 in these disease areas, high affinity, cell permeable and selective chemical probes are essential. DG013A 1, is a phosphinic acid tripeptide mimetic inhibitor with reported low nanomolar affinity for ERAP1. However, this chemotype is a privileged structure for binding to various metal-dependent peptidases and contains a highly charged phosphinic acid moiety, so it was unclear whether it would display the high selectivity and passive permeability required for a chemical probe. Therefore, we designed a new stereoselective route to synthesize a library of DG013A 1 analogues to determine the suitability of this compound as a cellular chemical probe to validate ERAP1 as a drug discovery target.

Identifiants

DOI: 10.1016/j.bmcl.2021.128050 PMID: 33887439 PMC: PMC8188423

pubmed: 33887439

pii: S0960-894X(21)00276-6

doi: 10.1016/j.bmcl.2021.128050

pmc: PMC8188423

pii:

doi:

Substances chimiques

Enzyme Inhibitors 0

Minor Histocompatibility Antigens 0

Oligopeptides 0

Phosphinic Acids 0

Aminopeptidases EC 3.4.11.-

ERAP1 protein, human EC 3.4.11.-

Types de publication

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

Langues

eng

Sous-ensembles de citation

Pagination

128050

Subventions

Organisme : Cancer Research UK

ID : C2739/A22897

Pays : United Kingdom

Organisme : Cancer Research UK

ID : C309/A11566

Pays : United Kingdom

Informations de copyright

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