Strategies for the late-stage modification of peptides and proteins

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Peptides and proteins are implicated in a multitude of crucial biological processes. The functional diversity of these molecules stems not only from the variety of canonical amino acids, but also the enzymatic decoration of native side-chains with structurally diverse post-translational modifications. Synthetic strategies which precisely tailor the structure and function of peptide and protein targets allow us to extend the biological diversity of these important biomolecules. We are interested in the development of residue-specific, late-stage modifications, including new strategies for protein bioconjugation, unnatural amino acid incorporation, and radiolabeling.

Synthetic approaches to peptide drug design

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Peptide drugs are an increasingly important class of therapeutic agents, often exhibiting higher target affinity and fewer side effects in comparison to their small molecule counterparts. Despite such promising bioactivity, peptide therapeutics are plagued by their susceptibility to proteolytic degradation, poor oral bioavailability, and limited cell permeability. We are interested in probing new synthetic strategies, including macrocyclization, peptide stapling, and chemoselective backbone modifications, to enhance the drug-like properties of bioactive peptides. Multi-disciplinary projects will involve solution- and solid-phase organic synthesis, structural and computational analysis, and biological screening of peptide analogues.

Synthetic organic methodology and reagent development

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Our ability to manipulate molecules and probe new areas of chemical space is intrinsically linked to the repertoire of chemical reagents and methodologies we have at our disposal. We are interested in the development of new strategies for the preparation of structurally complex and biologically relevant targets, particularly natural products. Inspired by the efficiency of nature, we hope to exploit innate chemical reactivity to minimize the number of synthetic steps required to reach a target molecule. The Malins lab will focus specifically on transformations which proceed through radical intermediates.

Chemoselective ligation tools for the synthesis of proteins and antibody-drug conjugates

Protein ligation website SchemeChemical protein synthesis provides unlimited flexibility for the design of engineered protein variants for the advancement of biological, medicinal, and materials science. Synthetic methods rely on our ability to precisely stitch together short peptide fragments in the presence of the diverse array of proteinogenic amino acid side-chains. We aim to explore versatile new chemical ligation strategies for the construction of native protein targets and discrete structural analogues. Such methodologies will extend the therapeutic potential of proteins and facilitate a greater understanding of the link between protein structure and function.