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KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity
Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acid...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540442/ https://www.ncbi.nlm.nih.gov/pubmed/34685408 http://dx.doi.org/10.3390/life11101037 |
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author | González-Bacerio, Jorge Arocha, Irina Aguado, Mirtha Elisa Méndez, Yanira Marsiccobetre, Sabrina Izquierdo, Maikel Rivera, Daniel G. Figarella, Katherine Uzcátegui, Néstor L. |
author_facet | González-Bacerio, Jorge Arocha, Irina Aguado, Mirtha Elisa Méndez, Yanira Marsiccobetre, Sabrina Izquierdo, Maikel Rivera, Daniel G. Figarella, Katherine Uzcátegui, Néstor L. |
author_sort | González-Bacerio, Jorge |
collection | PubMed |
description | Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite’s leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC(50) = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC(50) = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization. |
format | Online Article Text |
id | pubmed-8540442 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85404422021-10-24 KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity González-Bacerio, Jorge Arocha, Irina Aguado, Mirtha Elisa Méndez, Yanira Marsiccobetre, Sabrina Izquierdo, Maikel Rivera, Daniel G. Figarella, Katherine Uzcátegui, Néstor L. Life (Basel) Article Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite’s leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC(50) = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC(50) = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization. MDPI 2021-10-01 /pmc/articles/PMC8540442/ /pubmed/34685408 http://dx.doi.org/10.3390/life11101037 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article González-Bacerio, Jorge Arocha, Irina Aguado, Mirtha Elisa Méndez, Yanira Marsiccobetre, Sabrina Izquierdo, Maikel Rivera, Daniel G. Figarella, Katherine Uzcátegui, Néstor L. KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity |
title | KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity |
title_full | KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity |
title_fullStr | KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity |
title_full_unstemmed | KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity |
title_short | KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity |
title_sort | kbe009: a bestatin-like inhibitor of the trypanosoma cruzi acidic m17 aminopeptidase with in vitro anti-trypanosomal activity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540442/ https://www.ncbi.nlm.nih.gov/pubmed/34685408 http://dx.doi.org/10.3390/life11101037 |
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