Impact of the Recognition Part of Dipeptidyl Nitroalkene Compounds on the Inhibition Mechanism of Cysteine Proteases Cruzain and Cathepsin L
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Show full item recordcomunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/160292
comunitat-uji-handle3:10234/160293
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Title
Impact of the Recognition Part of Dipeptidyl Nitroalkene Compounds on the Inhibition Mechanism of Cysteine Proteases Cruzain and Cathepsin LAuthor (s)
Date
2023-05-05Publisher
American Chemical SocietyISSN
2155-5435Bibliographic citation
Arafet, K.; Royo, S.; Schirmeister, T.; Barthels, F.; González, F. V.; Moliner, V.Impact of the Recognition Part of Dipeptidyl Nitroalkene Compounds on the Inhibition Mechanism of Cysteine Proteases Cruzain and Cathepsin L. ACS Catal. 2023, 13, 9, 6289–6300. DOI: https://doi.org/10.1021/acscatal.3c01035Type
info:eu-repo/semantics/articlePublisher version
https://pubs.acs.org/doi/full/10.1021/acscatal.3c01035Version
info:eu-repo/semantics/publishedVersionSubject
Abstract
Cysteine proteases (CPs) are an important class of enzymes, many of which are responsible for several human diseases. For instance, cruzain of protozoan parasite Trypanosoma cruzi is responsible for the Chagas disease, ... [+]
Cysteine proteases (CPs) are an important class of enzymes, many of which are responsible for several human diseases. For instance, cruzain of protozoan parasite Trypanosoma cruzi is responsible for the Chagas disease, while the role of human cathepsin L is associated with some cancers or is a potential target for the treatment of COVID-19. However, despite paramount work carried out during the past years, the compounds that have been proposed so far show limited inhibitory action against these enzymes. We present a study of proposed covalent inhibitors of these two CPs, cruzain and cathepsin L, based on the design, synthesis, kinetic measurements, and QM/MM computational simulations on dipeptidyl nitroalkene compounds. The experimentally determined inhibition data, together with the analysis and the predicted inhibition constants derived from the free energy landscape of the full inhibition process, allowed describing the impact of the recognition part of these compounds and, in particular, the modifications on the P2 site. The designed compounds and, in particular, the one with a bulky group (Trp) at the P2 site show promising in vitro inhibition activities against cruzain and cathepsin L for use as a starting lead compound in the development of drugs with medical applications for the treatment of human diseases and future designs. [-]
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ACS catalysis, 2023, vol. 13, no 9Funder Name
Ministerio de Ciencia, Innovación y Universidades | Generalitat Valenciana | Universitat Jaume I | Generalitat Valenciana
Project code
PGC2021-23332OB-C21 | Grant PROMETEO CIPROM/2021/079 | IDIFEDER/2021/027 | UJI-B2020-03 | UJI-2021-71 | APOSTD/2020/015
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info:eu-repo/semantics/openAccess
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