Intrinsically Disordered Proteins: Perspective on COVID-19 Infection and Drug Discovery

Since the beginning of the COVID-19 pandemic caused by SARS-CoV-2, millions of patients have been diagnosed and many of them have died from the disease worldwide. The identification of novel therapeutic targets are of utmost significance for prevention and treatment of COVID-19. SARS-CoV-2 is a single-stranded RNA virus with a 30 kb genome packaged into a membrane-enveloped virion, transcribing several tens of proteins. The belief that the amino acid sequence of proteins determines their 3D structure which, in turn, determines their function has been a central principle of molecular biology for a long time. Recently, it has been increasingly realized, however, that there is a large group of proteins that lack a fixed or ordered 3D structure, yet they exhibit important biological activities─so-called intrinsically disordered proteins and protein regions (IDPs/IDRs). Disordered regions in viral proteins are generally associated with viral infectivity and pathogenicity because they endow the viral proteins the ability to easily and promiscuously bind to host proteins; therefore, the proteome of SARS-CoV-2 has been thoroughly examined for intrinsic disorder. It has been recognized that, in fact, the SARS-CoV-2 proteome exhibits significant levels of structural order, with only the nucleocapsid (N) structural protein and two of the nonstructural proteins being highly disordered. The spike (S) protein of SARS-CoV-2 exhibits significant levels of structural order, yet its predicted percentage of intrinsic disorder is still higher than that of the spike protein of SARS-CoV. Noteworthy, however, even though IDPs/IDRs are not common in the SARS-CoV-2 proteome, the existing ones play major roles in the functioning and virulence of the virus and are thus promising drug targets for rational antiviral drug design. Presented here is a COVID-19 perspective on the intrinsically disordered proteins, summarizing recent results on the SARS-CoV-2 proteome disorder features, their physiological and pathological relevance, and their prominence as prospective drug target sites.