Built to bind : biosynthetic strategies for the formation of small-molecule protease inhibitors

Covering: up to 2019 Inhibitors of proteases and related enzymes have versatile applications in medicine and other areas. They are used in the clinic e.g. for the treatment of cancer, hypertension, thrombosis, diabetes as well as viral and bacterial infections. Most of these drugs are produced synthetically but a substantial part of them has been developed from or are inspired by natural products. Protease inhibitors typically mimic the peptide substrates of the target enzymes and feature specialized moieties that specifically interact with catalytic residues in the active centre. Such moieties may consist of electrophilic warheads e.g. β-lactones, Michael systems, epoxyketones or β-lactams that are attacked by active site nucleophiles and generate covalent adducts. Metalloproteinase inhibitors often contain functional groups which facilitate the chelation of active site metal ions e.g. hydroxamates, carboxylates or phosphoramidates. Other reversible protease inhibitors feature γ-amino acids or ketomethylene pseudopeptides to form stable substrate or transition state analogs. The discovery of such functional groups in natural products has been extensively exploited by medicinal chemistry to generate synthetic protease inhibitors. However, the biosynthetic principles for many of these moieties have remained obscure until recently. This review summarizes the current knowledge on the biosynthesis of important and/or structurally interesting inhibitors of proteases and related enzymes. Understanding the genetic basis that directs the formation of the specialized, activity-conferring moieties in protease inhibitors will allow targeted genome mining for the discovery of new derivatives.

Medienart:

E-Artikel

Erscheinungsjahr:

2019

Erschienen:

2019

Enthalten in:

Zur Gesamtaufnahme - volume:36

Enthalten in:

Natural product reports - 36(2019), 12 vom: 11. Dez., Seite 1654-1686

Sprache:

Englisch

Beteiligte Personen:

Kaysser, Leonard [VerfasserIn]

Links:

Volltext

Themen:

Aldehydes
Alkenes
Biological Products
EC 3.4.-
Journal Article
Lactones
Peptide Hydrolases
Protease Inhibitors
Research Support, Non-U.S. Gov't
Review
Small Molecule Libraries

Anmerkungen:

Date Completed 30.04.2020

Date Revised 30.04.2020

published: Print

Citation Status MEDLINE

doi:

10.1039/c8np00095f

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM295977477