Browsing by Subject "Peptidomimetics"

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    Novel peptide inhibitors targeting CD40 and CD40L interaction: A potential for atherosclerosis therapy
    (Elsevier, 2023-11-14) Solanki, Kundan; Kumar, Ashutosh; Khan, Mohd Shahnawaz; Karthikeyan, Subramani; Atre, Rajat; Zhang, Kam Y. J.; Bezsonov, Evgeny; Obukhov, Alexander G.; Baig, Mirza S.; Anatomy, Cell Biology and Physiology, School of Medicine
    Atherosclerosis is a chronic inflammatory disease characterized by plaque build-up in the arteries, leading to the obstruction of blood flow. Macrophages are the primary immune cells found in the atherosclerotic lesions and are directly involved in atherosclerosis progression. Macrophages are derived from extravasating blood monocytes. The monocytic CD40 receptor is important for monocyte recruitment on the endothelium expressing the CD40 ligand (CD40L). Thus, targeting monocyte/macrophage interaction with the endothelium by inhibiting CD40-CD40L interaction may be a promising strategy for attenuating atherosclerosis. Monoclonal antibodies have been used against this target but shows various complications. We used an array of computer-aided drug discovery tools and molecular docking approaches to design a therapeutic inhibitory peptide that could efficiently bind to the critical residues (82Y, 84D, and 86N) on the CD40 receptor essential for the receptor's binding to CD40L. The initial screen identified a parent peptide with a high binding affinity to CD40, but the peptide exhibited a positive hepatotoxicity score. We then designed several novel peptidomimetic derivatives with higher binding affinities to CD40, good physicochemical properties, and negative hepatotoxicity as compared to the parent peptide. Furthermore, we conducted molecular dynamics simulations for both the apo and complexed forms of the receptor with ligand, and screened peptides to evaluate their stability. The designed peptidomimetic derivatives are promising therapeutics targeting the CD40-CD40L interaction and may potentially be used to attenuate atherosclerosis.
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    β-Bracelets: Macrocyclic cross-β epitope mimics based on a tau conformational strain
    (American Chemical Society, 2023) Rajewski, Benjamin H.; Makwana, Kamlesh M.; Angera, Isaac J.; Geremia, Danielle K.; Zepeda, Anna R.; Hallinan, Grace I.; Vidal, Ruben; Ghetti, Bernardino; Serrano, Arnaldo L.; Del Valle, Juan R.; Pathology and Laboratory Medicine, School of Medicine
    The aggregation of misfolded tau into neurotoxic fibrils is linked to the progression of Alzheimer’s disease (AD) and related tauopathies. Disease-associated conformations of filamentous tau are characterized by hydrophobic interactions between sidechains on unique and distant β-strand modules within each protomer. Here, we report the design and diversity-oriented synthesis of β-arch peptide macrocycles comprised of the aggregation-prone PHF6 hexapeptide of tau and the cross-β module specific to the AD tau fold. Termed “β-bracelets”, these proteomimetics assemble in a sequence- and macrocycle-dependent fashion, resulting in amyloid-like fibrils that feature in-register parallel β-sheet structure. Backbone N-amination of a selected β-bracelet affords soluble inhibitors of tau aggregation. We further demonstrate that the N-aminated macrocycles block the prion-like cellular seeding activity of recombinant tau as well as mature fibrils from AD patient extracts. These studies establish β-bracelets as a new class of cross-β epitope mimic and demonstrate their utility in the rational design of molecules targeting amyloid propagation and seeding.