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In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in Escherichia coli as Leishmania amazonensis Arginase Inhibitors
Arginase is a metalloenzyme that plays a central role in Leishmania infections. Previously, rosmarinic and caffeic acids were described as antileishmanial agents and as Leishmania amazonensis arginase inhibitors. Here, we describe the inhibition of arginase in L. amazonensis by rosmarinic acid analo...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9504950/ https://www.ncbi.nlm.nih.gov/pubmed/36145452 http://dx.doi.org/10.3390/pathogens11091020 |
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author | Come, Julio Abel Alfredo dos Santos Simone Zhuang, Yibin Li, Tianzhen Brogi, Simone Gemma, Sandra Liu, Tao da Silva, Edson Roberto |
author_facet | Come, Julio Abel Alfredo dos Santos Simone Zhuang, Yibin Li, Tianzhen Brogi, Simone Gemma, Sandra Liu, Tao da Silva, Edson Roberto |
author_sort | Come, Julio Abel Alfredo dos Santos Simone |
collection | PubMed |
description | Arginase is a metalloenzyme that plays a central role in Leishmania infections. Previously, rosmarinic and caffeic acids were described as antileishmanial agents and as Leishmania amazonensis arginase inhibitors. Here, we describe the inhibition of arginase in L. amazonensis by rosmarinic acid analogs (1–7) and new caffeic acid-derived amides (8–10). Caffeic acid esters and amides were produced by means of an engineered synthesis in E. coli and tested against L. amazonensis arginase. New amides (8–10) were biosynthesized in E. coli cultured with 2 mM of different combinations of feeding substrates. The most potent arginase inhibitors showed Ki(s) ranging from 2 to 5.7 μM. Compounds 2–4 and 7 inhibited L. amazonensis arginase (L-ARG) through a noncompetitive mechanism whilst compound 9 showed a competitive inhibition. By applying an in silico protocol, we determined the binding mode of compound 9. The competitive inhibitor of L-ARG targeted the key residues within the binding site of the enzyme, establishing a metal coordination bond with the metal ions and a series of hydrophobic and polar contacts supporting its micromolar inhibition of L-ARG. These results highlight that dihydroxycinnamic-derived compounds can be used as the basis for developing new drugs using a powerful tool based on the biosynthesis of arginase inhibitors. |
format | Online Article Text |
id | pubmed-9504950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95049502022-09-24 In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in Escherichia coli as Leishmania amazonensis Arginase Inhibitors Come, Julio Abel Alfredo dos Santos Simone Zhuang, Yibin Li, Tianzhen Brogi, Simone Gemma, Sandra Liu, Tao da Silva, Edson Roberto Pathogens Article Arginase is a metalloenzyme that plays a central role in Leishmania infections. Previously, rosmarinic and caffeic acids were described as antileishmanial agents and as Leishmania amazonensis arginase inhibitors. Here, we describe the inhibition of arginase in L. amazonensis by rosmarinic acid analogs (1–7) and new caffeic acid-derived amides (8–10). Caffeic acid esters and amides were produced by means of an engineered synthesis in E. coli and tested against L. amazonensis arginase. New amides (8–10) were biosynthesized in E. coli cultured with 2 mM of different combinations of feeding substrates. The most potent arginase inhibitors showed Ki(s) ranging from 2 to 5.7 μM. Compounds 2–4 and 7 inhibited L. amazonensis arginase (L-ARG) through a noncompetitive mechanism whilst compound 9 showed a competitive inhibition. By applying an in silico protocol, we determined the binding mode of compound 9. The competitive inhibitor of L-ARG targeted the key residues within the binding site of the enzyme, establishing a metal coordination bond with the metal ions and a series of hydrophobic and polar contacts supporting its micromolar inhibition of L-ARG. These results highlight that dihydroxycinnamic-derived compounds can be used as the basis for developing new drugs using a powerful tool based on the biosynthesis of arginase inhibitors. MDPI 2022-09-07 /pmc/articles/PMC9504950/ /pubmed/36145452 http://dx.doi.org/10.3390/pathogens11091020 Text en © 2022 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 Come, Julio Abel Alfredo dos Santos Simone Zhuang, Yibin Li, Tianzhen Brogi, Simone Gemma, Sandra Liu, Tao da Silva, Edson Roberto In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in Escherichia coli as Leishmania amazonensis Arginase Inhibitors |
title | In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in Escherichia coli as Leishmania amazonensis Arginase Inhibitors |
title_full | In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in Escherichia coli as Leishmania amazonensis Arginase Inhibitors |
title_fullStr | In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in Escherichia coli as Leishmania amazonensis Arginase Inhibitors |
title_full_unstemmed | In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in Escherichia coli as Leishmania amazonensis Arginase Inhibitors |
title_short | In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in Escherichia coli as Leishmania amazonensis Arginase Inhibitors |
title_sort | in vitro and in silico analyses of new cinnamid and rosmarinic acid-derived compounds biosynthesized in escherichia coli as leishmania amazonensis arginase inhibitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9504950/ https://www.ncbi.nlm.nih.gov/pubmed/36145452 http://dx.doi.org/10.3390/pathogens11091020 |
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