Antimicrobial Peptides
Antimicrobial peptides (AMPs) are promising alternatives to combat antibiotic resistance, but their short half-life due to protease degradation limits their effectiveness. This study presents all-D-amino acid-based peptides, P4C and P5C, which are protease-resistant, noncytotoxic, nonhemolytic, and more potent against ESKAPE pathogens compared to their L-analogues. MD simulations show that the L → D conversion slightly improves antimicrobial activity but significantly reduces peptide-protease binding affinity. The D-peptides form an inactive complex with proteases, explaining their stability. This insight may aid in designing protease-resistant AMPs.
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Peptidomimetics
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The impact of incorporating geminally dimethyl-substituted γ-amino acids—γâ‚‚,â‚‚, γ₃,₃, and γâ‚„,â‚„—at the (i + 2) position in an αγ C12 turn segment within a model octapeptide was investigated. Conformational analysis (NMR, CD, IR) and ab initio calculations revealed that γ₃,₃ and γâ‚„,â‚„ effectively stabilized β-hairpins, whereas γâ‚‚,â‚‚ failed due to steric hindrance at Cα. Backbone geminal substitutions influenced torsion angles, leading to distinct conformational preferences. Folded hairpins were energetically favored (~8–9 kcal/mol) over unfolded peptides, independent of N-terminal protection. These insights will aid the rational design of foldamers.
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The Journal of Organic Chemistry 2021 86 (17), 11310-11323
Peptide Self Assembly
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Chirality is fundamental to nature, from simple amino acids to complex structures like proteins, DNA, and RNA. Proteins typically form right-handed helices due to the L-configuration of amino acids, while ambidextrous helices are rare. Here, we present the first observation of ambidextrous and left-handed helices in chiral nonapeptides P1–P3, composed of L α amino acids and an achiral γ residue. The achiral γ residue, capable of adopting both helicities, induces handedness reversal in adjacent residues, with a single water molecule stabilizing ambidextrous helices in P1 and P2. Experiments and DFT calculations reveal that geminal disubstitution position critically influences helical conformations.
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