ABSTRACT
Besides its prominent role in cell proliferation, cyclin-dependent kinases (CDKs) are key players in viral infections as both DNA and RNA viruses modify CDK function to favor viral replication. Recently, a number of specific pharmacological CDK inhibitors have been developed and approved for cancer treatment. The repurposing of these specific CDK inhibitors for the treatment of viral infections may represent a novel effective therapeutic strategy to combat old and emergent viruses. In this review, we describe the role, mechanisms of action, and potential of CDKs as antiviral drug targets. We also discuss the current clinical state of novel specific CDK inhibitors, focusing on their putative use as antivirals, especially against new emerging viruses.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Cyclin-Dependent Kinases/antagonists & inhibitors , SARS-CoV-2/drug effects , Virus Diseases/drug therapy , Animals , Antiviral Agents/therapeutic use , Cyclin-Dependent Kinases/physiology , Drug Repositioning , Humans , Virus Diseases/enzymologySubject(s)
COVID-19 Drug Treatment , Cyclin-Dependent Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , SARS-CoV-2/drug effects , COVID-19/enzymology , Cell Cycle/drug effects , Cell Division/drug effects , Humans , Protein Kinase Inhibitors/pharmacology , SARS-CoV-2/physiology , Virus Replication/drug effectsABSTRACT
The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.