Peptides are short sequences of amino acids that can mimic the shape, and therefore function, of larger proteins. Peptide therapeutics can potentially be used for the treatment of a wide range diseases such as HIV, diabetes, and cancer. Peptides are naturally broken down by enzymes within the body through a process called proteolysis, but the introduction of unnatural amino acids into the sequence can slow this process, potentially increasing the lifetime of peptide therapeutics. We have examined the impact of the incorporation of α-alkylated amino acids, unnatural amino acids in which the α-proton is replaced by an alkyl side chain, into short, β-hairpin peptides. Four α-alkylated amino acid derivatives with varying side chain lengths were incorporated into peptides using Fmoc solid-phase peptide synthesis. These peptides were then analyzed using homonuclear multidimensional-NMR spectroscopy to determine the propensity of the unnatural amino acids to promote a β -hairpin folded conformation. These analyses showed that the α-alkylated amino acid with two side chains consisting of one carbon unit completely disrupted the folding population of the model system. However, increasing the side chain length of the α-alkylated amino acids to two or more carbon units restores some of this folded stability.

Thermodynamic and structural impact of α,α-dialkylated residue incorporation in a β-hairpin peptide

253rd National Meeting (2017)

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