Avoiding Regions Symptomatic of Conformational and Functional Flexibility to Identify Antiviral Targets in Current and Future Coronaviruses

Rahaman, Jordon; Siltberg-Liberles, Jessica

The flexibility trait of many viral proteins is a complicating factor in vaccine development. For instance, Dengue virus exhibits serotype-specific antibody affinity that causes antibodydependent enhancement, an obstacle in the development of Dengue vaccines that protects against all four serotypes (Flipse and Smit 2015) . To overcome the hurdle posed by structural flexibility, we propose an additional screening step in identifying potential vaccine or antiviral targets that considers the structural flexibility of the viral proteins. The Structural Genomics Initiatives increased their success rate by excluding proteins predicted to be structurally disordered (Slabinski et al. 2007) . A similar approach can perhaps benefit vaccine development. Furthermore, to make this approach robust to potential mutations, minimizing loss in efficacy or resistance, the evolutionary context of sequence and structure must be considered. Thus, we suggest expanding the concept of broadly neutralizing vaccines/antivirals by increasing the diversity of viruses considered if possible. Sites conserved for sequence, structure, and with low disorder propensity among diverse virus protein homologs are very likely to be constrained from 1) changing sequence on evolutionary time scales and 2) undergoing real-time structural transitions. These sites have potential as targets for broad-specificity antivirals or vaccines because conservation makes them broad-specificity and low dynamics avoids targeting a conformational ensemble, which is not only difficult (Yu et al. 2016) , but that may change as the sequence diverges (Siltberg-Liberles et al. 2011) .