Chemoselective Sulfonyl-Fluoride Exchange (SuFEx)- induced macrocyclization of tyrosine-containing peptides & identification of a conserved Asx helix cap motif in paramyxoviral fusion glycoproteins
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[EMBARGOED UNTIL 08/01/2026] This thesis presents two distinct projects involving peptide chemistry. In the first project, a novel chemoselective macrocyclization method for tyrosinecontaining peptides was developed using Sulfonyl Fluoride Exchange (SuFEx) chemistry. By incorporating a SuFEx-able handle at the N-terminus and targeting the phenolic hydroxyl group of tyrosine, efficient macrocyclization was achieved under mild aqueous conditions. The reaction demonstrated high yields, excellent chemoselectivity, and compatibility with all native amino acids. Cyclization significantly improved the stability and protease resistance of the peptides, as confirmed by biophysical characterization and biological assays. The method was further applied to generate a library of RGD-based cyclic peptides, including analogues of Cilengitide, which exhibited promising anti-adhesion activity in cellbased assays. The second project focuses on the structural characterization of a conserved Asx (aspartate/asparagine) helix cap motif in paramyxoviral fusion glycoproteins. Fusion proteins from three viruses--HPIV3, HeV, and MeV--were studied to understand the role of this motif in stabilizing the six-helix bundle (6-HB) postfusion core. Peptides representing the HRN and HRC domains were synthesized and analyzed using circular dichroism and X-ray crystallography. Mutational analysis of the HRC domain confirmed the functional importance of the Asx cap in promoting helical structure and stability. The findings suggest that this conserved cap motif plays a critical role in the fusion process and may serve as a structural target for therapeutic intervention across the paramyxovirus family. Together, these studies advance the fields of peptide-based drug design and viral fusion protein engineering, offering new tools for macrocyclic peptide synthesis and insights into conserved structural elements of class I viral fusion machinery.
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M.S.