Influence of <i>N</i>-Methylation and Conformation on Almiramide Anti-Leishmanial Activity
The almiramide <i>N</i>-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of <i>N</i>-methylation and conformation on activity against various strains of le...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/12/3606 |
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| author | Anh Minh Thao Nguyen Skye Brettell Noélie Douanne Claudia Duquette Audrey Corbeil Emanuella F. Fajardo Martin Olivier Christopher Fernandez-Prada William D. Lubell |
| author_facet | Anh Minh Thao Nguyen Skye Brettell Noélie Douanne Claudia Duquette Audrey Corbeil Emanuella F. Fajardo Martin Olivier Christopher Fernandez-Prada William D. Lubell |
| author_sort | Anh Minh Thao Nguyen |
| collection | DOAJ |
| description | The almiramide <i>N</i>-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of <i>N</i>-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 <i>N</i>-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. |
| first_indexed | 2024-03-10T10:28:49Z |
| format | Article |
| id | doaj.art-f0daccf1924543e89ac235908139a86e |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T10:28:49Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f0daccf1924543e89ac235908139a86e2023-11-21T23:51:57ZengMDPI AGMolecules1420-30492021-06-012612360610.3390/molecules26123606Influence of <i>N</i>-Methylation and Conformation on Almiramide Anti-Leishmanial ActivityAnh Minh Thao Nguyen0Skye Brettell1Noélie Douanne2Claudia Duquette3Audrey Corbeil4Emanuella F. Fajardo5Martin Olivier6Christopher Fernandez-Prada7William D. Lubell8Départements de chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, CanadaDépartements de chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, CanadaDépartement de Pathologie et Microbiologie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, CanadaDépartement de Pathologie et Microbiologie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, CanadaDépartement de Pathologie et Microbiologie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, CanadaDepartment of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, CanadaDepartment of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, CanadaDépartement de Pathologie et Microbiologie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, CanadaDépartements de chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, CanadaThe almiramide <i>N</i>-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of <i>N</i>-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 <i>N</i>-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.https://www.mdpi.com/1420-3049/26/12/3606almiramideleishmaniasis<i>N</i>-methylated peptide |
| spellingShingle | Anh Minh Thao Nguyen Skye Brettell Noélie Douanne Claudia Duquette Audrey Corbeil Emanuella F. Fajardo Martin Olivier Christopher Fernandez-Prada William D. Lubell Influence of <i>N</i>-Methylation and Conformation on Almiramide Anti-Leishmanial Activity Molecules almiramide leishmaniasis <i>N</i>-methylated peptide |
| title | Influence of <i>N</i>-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
| title_full | Influence of <i>N</i>-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
| title_fullStr | Influence of <i>N</i>-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
| title_full_unstemmed | Influence of <i>N</i>-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
| title_short | Influence of <i>N</i>-Methylation and Conformation on Almiramide Anti-Leishmanial Activity |
| title_sort | influence of i n i methylation and conformation on almiramide anti leishmanial activity |
| topic | almiramide leishmaniasis <i>N</i>-methylated peptide |
| url | https://www.mdpi.com/1420-3049/26/12/3606 |
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