Alkylated histidine based short cationic antifungal peptides: synthesis, biological evaluation and mechanistic investigations

Mittal, Sherry; Kaur, Sarabjit; Swami, Anuradha; Maurya, Indresh Kumar; Jain, Rahul; Wangoo, Nishima; Sharma, Rohit K.

doi:10.1039/c6ra05883c

Cited by 20 publications

(6 citation statements)

References 39 publications

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“…A literature survey revealed that the number of antifungal peptides (AFPs) and antimicrobial peptides (AMPs) exhibiting antifungal activity contain Trp, Arg, His, Phe, Lys and Leu amino acids in common and in abundance. The presence of these amino acids and sometimes their repeat in specific sequences play a pivotal role in the antifungal profile of the peptides [41][42][43]. Notably, out of all the compounds designed in the present study, the most active compounds (L19-L27) were also found to contain tripeptide sequences comprising mainly of amino acids Trp, Arg, His, and Phe.…”

Section: Ligand Design and Molecular Docking Studiesmentioning

confidence: 69%

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2020

Biointerface Res Appl Chem

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In the present work, a library of 117 coumarin-amino acid(s) conjugates was designed, and molecular docking study was performed to investigate their possible role as fungal integrin like receptor antagonists. The objective of this study is in-silico designing and docking of coumarin-amino acid conjugates against integrin like protein of Cryptococcus neoformans. In the absence of a crystallographic structure of integrin of the fungal pathogen, a homology model of protein OXH63806.1 of Cryptococcus neoformans was developed using the currently available X-ray structure of human integrin as a template. The quality of the 3D model obtained by homology modeling was evaluated by the PROCHECK program. A docking study using coumarin-amino acid(s) conjugates as ligands on the binding site of the modeled receptor was carried out to understand the protein-ligand binding interactions. Some of the compounds have shown very good binding energies ranging from-10.32 to-10.94 Kcal/mol towards the target receptor. These results may be helpful in the designing and development of new antifungal agents as integrin like protein antagonists.

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Section: Ligand Design and Molecular Docking Studiesmentioning

confidence: 69%

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2020

Biointerface Res Appl Chem

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“…The precursor N ‐α‐Boc‐2‐alkyl‐L‐histidines ( 5i–vi ), needed for the synthesis of proposed tripeptides, was attained using four step synthetic route (Scheme ) . Firstly, the amine terminus of L‐His‐OMe dihydrochloride ( 1 ) was protected using trifluroacetic anhydride to afford compound ( 2 ) which was further subjected to regiospecfic alkylation reaction at C‐2 position of histidine's imidazole ring . The reaction follows nucleophilic addition of an alkyl radical, generated in situ from alkyl carboxylic acid by silver catalyzed oxidative decarboxylation using ammonium persulfate to afford trifluroacetyl protected component ( 3i–vi ).…”

Section: Resultsmentioning

confidence: 99%

Insights into Mechanistic and Synergistic Aspects of Novel Synthetic Short Cationic Antibacterial Peptides

et al. 2016

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Two series of short cationic antimicrobial peptides (CAMPs) in which modification of the imidazole ring of histidine by bulkier alkyl substituents was done using regiospecific and radical‐mediated alkylation. The synthesized CAMPs were evaluated for their antibacterial efficacy using different bacterial strains. In particular, CAMP 11 i was found to be most active against L. monocytogenes and other CAMPs such as 10 e and 11 g exhibited moderate activity against S. aureus.The most active compounds were tested against Hek‐293 and HeLa cells with active CAMPs 11 i and 11 g with calculation of selectivity index against the L. monocytogenesand S. aureus, respectively as compared to mammalian cells. The SEM studies were also performed which confirmed the disruption of cell wall of treated bacteria using CAMP 11 i at its MIC concentration. The selectivity of active peptides towards bacterial cells in comparison to mammalian cells was checked using tryptophan quenching studies on small unilamellar vesicles. The results were found to be perfectly in corroboration with the differences between bacterial and mammalian cell membrane composition, thereby, indicating that these peptides kill the bacterial cells via conjugation with the cell membrane. Synergy studies of CAMPs in combination with known clinical antibacterial drugs against L. monocytogenes further displayed enhanced antibacterial efficacy.

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“…It was suggested that this class of peptides act by selectively binding to negatively charged microbial membranes over the neutral mammalian membranes, and disrupt the cell membranes leading to lysis of the microbial cells. 144 Mittal et al 145 reported another class of modified histidine containing short cationic antimicrobial peptides (Figure 8). Peptides were screened against S. aureus, Listeria monocytogenes, E. coli, Vibrio cholerae and Enterococcus 165 showed the most significant activity against L. monocytogenes with IC 50 values of 9.3 μg/ml, but was inactive against all other strains.…”

Section: Antimicrobial Activitymentioning

confidence: 99%

Design, synthesis, and applications of ring‐functionalized histidines in peptide‐based medicinal chemistry and drug discovery

Sharma

Mahindra

et al. 2023

Medicinal Research Reviews

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Modified and synthetic α-amino acids are known to show diverse applications. Histidine, which possesses numerous applications when subjected to synthetic modifications, is one such amino acid. The utility of modified histidines varies widely from remarkable biological activities to catalysis, and from nanotechnology to polymer chemistry. This renders histidine residue an important place in scientific research. Histidine is a well-studied scaffold and constitutes the active site of various enzymes catalyzing important reactions in the biological systems. A rational modification in histidine structure with a distinctly developed protocol extensively changes its physical and chemical properties. The utilization of modified histidines in search of potent, target selective and proteostable scaffolds is vital in the development of bioactive peptides with enhanced drug-likeliness. This review is a compilation and analysis of reported side-chain ring modifications at histidine followed by applications of ring-modified histidines in the synthesis of various categories of bioactive peptides and peptidomimetics.

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Alkylated histidine based short cationic antifungal peptides: synthesis, biological evaluation and mechanistic investigations

Abstract: Novel antifungal peptides are described with some peptides exhibiting selective activity againstC. neoformans. Cytotoxicity and mechanistic studies reveal their applicability as effective antimicrobials with less susceptibility to drug resistance.

Cited by 20 publications

References 39 publications

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Insights into Mechanistic and Synergistic Aspects of Novel Synthetic Short Cationic Antibacterial Peptides

Design, synthesis, and applications of ring‐functionalized histidines in peptide‐based medicinal chemistry and drug discovery

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