Targeting Viral Surface Proteins through Structure-Based Design

Abstract

The emergence of novel viral infections of zoonotic origin and mutations of existing human pathogenic viruses represent a serious concern for public health. It warrants the establishment of better interventions and protective therapies to combat the virus and prevent its spread. Surface glycoproteins catalyzing the fusion of viral particles and host cells have proven to be an excellent target for antivirals as well as vaccines. This review focuses on recent advances for computational structure-based design of antivirals and vaccines targeting viral fusion machinery to control seasonal and emerging respiratory viruses.

Novel Vaccines and Drugs That Target the Surface Glycoproteins of Influenza Viruses, RSV, Parainfluenza Viruses, and SARS-CoV-2

“…The review article by Tripp and Stambas [2] provides a general overview of vaccines being developed against all of these respiratory viruses, including influenza viruses. The review by Narkhede et al [1] describes recent advances in computational structure-based design of glycoprotein-focused vaccines, including the influenza HA protein. Nagashima and Mousa [3] review efforts to expand the breadth of protection of HA-based vaccines.…”

“…Expanded discussions of successes using mosaic and computationally optimized broadly reactive antigens (COBRAs) are described [3]. Other strategies for developing universal influenza vaccines by focusing on responses to the stalk include headless HA vaccines, chimeric HA vaccines, and hyper-glycosylated antigens [1,3].…”

“…The modes of action of HA inhibitors are to interfere with HA binding with cellular receptors or fusion, therefore, these inhibitors target the globular head, containing the receptor-binding domain, or the stalk, containing the fusion peptide, respectively. Computational design has assisted in the development of HA protein inhibitors that disrupt protein-protein interactions and, thereby, inhibit receptor binding and/or membrane fusion [1]. However, targeting the HA protein with small-molecule drugs remains challenging due to the emergence of drug-resistant substitutions, which is more likely when targeting broad structural features as opposed to an enzyme active site.…”

“…As reviewed in Narkhede et al [1], these viruses contain a structural class I fusionmediating glycoprotein that has a metastable prefusion conformation. The fusion proteins of these viruses are as follows: influenza A and B virus (hemagglutinin, HA); RSV, HMPV, and the HPIVs (fusion, F); and SARS-CoV-2 (spike, S).…”

How Antibodies Recognize Pathogenic Viruses: Structural Correlates of Antibody Neutralization of HIV-1, SARS-CoV-2, and Zika

“…For many viruses, the ability to produce a cross reactive response either to many strains of the same virus or to different viruses in the same group is necessary for complete protection from disease, presenting a challenge for vaccine design [ 156 ]. Therefore, the structure-guided development of small molecules, peptides, and protein decoys as therapeutics is a complementary strategy for treating viral infection [ 157 ].…”