Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents.
Cysteine Endopeptidases
Cysteine Proteases
/ metabolism
Cysteine Proteinase Inhibitors
/ pharmacology
Dipeptides
/ pharmacology
Humans
Leishmania mexicana
/ enzymology
Nitriles
/ pharmacology
Protozoan Proteins
/ antagonists & inhibitors
Trypanocidal Agents
/ pharmacology
Trypanosoma cruzi
/ enzymology
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
29
08
2019
accepted:
30
01
2020
entrez:
13
3
2020
pubmed:
13
3
2020
medline:
13
5
2020
Statut:
epublish
Résumé
The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1´ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.
Identifiants
pubmed: 32163418
doi: 10.1371/journal.pntd.0007755
pii: PNTD-D-19-01493
pmc: PMC7067379
doi:
Substances chimiques
Cysteine Proteinase Inhibitors
0
Dipeptides
0
Nitriles
0
Protozoan Proteins
0
Trypanocidal Agents
0
Cysteine Proteases
EC 3.4.-
Cysteine Endopeptidases
EC 3.4.22.-
cruzipain
EC 3.4.22.51
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0007755Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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