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Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity
The almiramide N-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of N-methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxic...
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/PMC8231256/ https://www.ncbi.nlm.nih.gov/pubmed/34204673 http://dx.doi.org/10.3390/molecules26123606 |
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author | Nguyen, Anh Minh Thao Brettell, Skye Douanne, Noélie Duquette, Claudia Corbeil, Audrey Fajardo, Emanuella F. Olivier, Martin Fernandez-Prada, Christopher Lubell, William D. |
author_facet | Nguyen, Anh Minh Thao Brettell, Skye Douanne, Noélie Duquette, Claudia Corbeil, Audrey Fajardo, Emanuella F. Olivier, Martin Fernandez-Prada, Christopher Lubell, William D. |
author_sort | Nguyen, Anh Minh Thao |
collection | PubMed |
description | The almiramide N-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of N-methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated that derivatives with a single methyl group on either the first or fifth residue amide nitrogen exhibited greater activity than the permethylated peptides and relatively high potency against resistant strains. Replacement of amino amide residues in the peptide, by turn inducing α amino γ lactam (Agl) and N-aminoimidazalone (Nai) counterparts, reduced typically anti-parasitic activity; however, peptide amides possessing Agl residues at the second residue retained significant potency in the unmethylated and permethylated series. Systematic study of the effects of methylation and turn geometry on anti-parasitic activity indicated the relevance of an extended conformer about the central residues, and conformational mobility by tertiary amide isomerization and turn geometry at the extremities of the active peptides. |
format | Online Article Text |
id | pubmed-8231256 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82312562021-06-26 Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity Nguyen, Anh Minh Thao Brettell, Skye Douanne, Noélie Duquette, Claudia Corbeil, Audrey Fajardo, Emanuella F. Olivier, Martin Fernandez-Prada, Christopher Lubell, William D. Molecules Article The almiramide N-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of N-methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated that derivatives with a single methyl group on either the first or fifth residue amide nitrogen exhibited greater activity than the permethylated peptides and relatively high potency against resistant strains. Replacement of amino amide residues in the peptide, by turn inducing α amino γ lactam (Agl) and N-aminoimidazalone (Nai) counterparts, reduced typically anti-parasitic activity; however, peptide amides possessing Agl residues at the second residue retained significant potency in the unmethylated and permethylated series. Systematic study of the effects of methylation and turn geometry on anti-parasitic activity indicated the relevance of an extended conformer about the central residues, and conformational mobility by tertiary amide isomerization and turn geometry at the extremities of the active peptides. MDPI 2021-06-12 /pmc/articles/PMC8231256/ /pubmed/34204673 http://dx.doi.org/10.3390/molecules26123606 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 Nguyen, Anh Minh Thao Brettell, Skye Douanne, Noélie Duquette, Claudia Corbeil, Audrey Fajardo, Emanuella F. Olivier, Martin Fernandez-Prada, Christopher Lubell, William D. Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
title | Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
title_full | Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
title_fullStr | Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
title_full_unstemmed | Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
title_short | Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
title_sort | influence of n-methylation and conformation on almiramide anti-leishmanial activity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231256/ https://www.ncbi.nlm.nih.gov/pubmed/34204673 http://dx.doi.org/10.3390/molecules26123606 |
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