SARS-CoV-2 3CL protease interaction with host factors - identifying novel drug targets

SARS-CoV-2 3CL protease (3CL^Pro) plays crucial role in the viral life cycle by releasing different non-structural proteins from viral polyproteins. It also interacts with several host factors and orchestrates different host cell pathways by cleaving key cellular factors involved in immune modulation, cellular metabolism and cell death. Several host factors have been identified as high confidence substrates of 3CL^Pro which regulates host cellular environment both in an enzyme-dependent and enzyme-independent manner. Degradation of RIG-I, TRIM25 and NLRP12 by 3CL^Pro downregulates the innate immune response while enzyme-independent interaction with host factors like MAVS promote both its degradation and upregulation. Cellular transcription and translation are altered by interaction of 3CL^Pro with host proteins. It affects cell-death by interacting with factors like Gal-8, NDP52 and GSDMD. Post-COVID neurodegenerative disorders have been observed due to the downregulation of neuronal factors like NEMO and UBE3A. The spectrum of 3CL^Pro interaction with the key host factors indicates the alternate role of viral protease that modulates host response during infection. Several 3CL^Pro targets and their cleavage sites on the target proteins have been identified. This review highlights the crosstalk between 3CL^Pro and different host factors as possible alternate therapeutic targets to inhibit the viral propagation as well as address the post COVID clinical issues.