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Rational Design of Viral Inhibitors: Application to SARS
Institution: University of Texas Medical Branch (UTMB), Galveston, TX
Principal Investigator: Vincent Hilser, PhD
Co-Investigators: Shinji Makino, PhD - UTMB, Galveston, TX
Expected Product:Demonstrate the efficacy of computationally-designed peptides in cell-based assays involving SARS.
Description: The development of rational strategies that can effectively target and prevent viral infection is a strategic objective of the WRCE. Although design efforts have met with periodic success, a key shortcoming is the difficulty associated with the dynamic nature of protein conformation. Namely, the viral protein targets (usually envelope proteins) do not behave as the static structures that are used to depict them. Instead, these proteins are dynamic and experience conformational fluctuations. This poses the obvious problem of designing a ligand for a structurally heterogenous target. Here this problem is addressed with a unique computational approach that has been developed over the past decade. Recent studies on the design of inhibitors to the human prion protein (PrP), have provided proof-of-principle that a new computational algorithm called COREX_Design is able to: (1) identify ‘thermodynamically compatible” potential binding site(s); (2) design a conformationally constrained, disulfide cross-linked cyclic peptide ligand that is structurally compatible with this site; and (3) optimize the sequence to maximize the conformational compatibility between the protein and the peptide. This tool was able to successfully design potent inhibitors of infectious amyloids of PrP. The goal of this project is to demonstrate proof-of-principle
that COREX_Design can be applied to the development of antiviral
agents. Although this new design tool can in principle be applied
to any system where structural information is known about the target,
it is applied here to the spike protein receptor binding domain
of the severe acute respiratory syndrome (SARS) coronavirus. We
will demonstrate the efficacy of the designed peptides in cell-based
assays.
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