Targeting viral proteins for restraining SARS-CoV-2: focusing lens on viral proteins beyond spike for discovering new drug targets.

INTRODUCTION: Emergence of highly infectious SARS-CoV-2 variants are reducing protection provided by current vaccines, requiring constant updates in antiviral approaches. The virus encodes four structural and sixteen nonstructural proteins which play important roles in viral genome replication and transcription, virion assembly, release , entry into cells, and compromising host cellular defenses. As alien proteins to host cells, many viral proteins represent potential targets for combating the SARS-CoV-2. AREAS COVERED: Based on literature from PubMed and Web of Science databases, the authors summarize the typical characteristics of SARS-CoV-2 from the whole viral particle to the individual viral proteins and their corresponding functions in virus life cycle. The authors also discuss the potential and emerging targeted interventions to curb virus replication and spread in detail to provide unique insights into SARS-CoV-2 infection and countermeasures against it. EXPERT OPINION: Our comprehensive analysis highlights the rationale to focus on non-spike viral proteins that are less mutated but have important functions. Examples of this include: structural proteins (e.g. nucleocapsid protein, envelope protein) and extensively-concerned nonstructural proteins (e.g. NSP3, NSP5, NSP12) along with the ones with relatively less attention (e.g. NSP1, NSP10, NSP14 and NSP16), for developing novel drugs to overcome resistance of SARS-CoV-2 variants to preexisting vaccines and antibody-based treatments.

Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load.

Despite extensive efforts, COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large. Vaccination is an effective approach to curb virus spread, but several variants (e.g., delta, delta plus, omicron, and IHU) appear to weaken or possibly escape immune protection. Thus, novel and quickly scalable approaches to restrain SARS-CoV-2 are urgently needed. Multiple evidences showed thermal sensitivity of SARS-CoV-2 and negative correlation between environmental temperature and COVID-19 transmission with unknown mechanism. Here, we reveal a potential mechanism by which mild heat treatment destabilizes the wild-type RNA-dependent RNA polymerase (also known as nonstructural protein 12 (NSP12)) of SARS-CoV-2 as well as the P323L mutant commonly found in SARS-CoV-2 variants, including omicron and IHU. Mechanistically, heat treatment promotes E3 ubiquitin ligase ZNF598-dependent NSP12 ubiquitination leading to proteasomal degradation and significantly decreases SARS-CoV-2 RNA copy number and viral titer. A mild daily heat treatment maintains low levels of both wild-type and P323L mutant of NSP12, suggesting clinical potential. Collectively, this novel mechanism, heat-induced NSP12 degradation, suggests a prospective heat-based intervention against SARS-CoV-2.