A Mini-Review on the Common Antiviral Drug Targets of Coronavirus

Abstract

Coronaviruses in general are a zoonotic pathogen with significant cross-species transmission. They are widely distributed in nature and have recently become a major threat to global public health. Vaccines are the preferred strategy for the prevention of coronaviruses. However, the rapid rate of virus mutation, large number of prevalent strains, and lag in vaccine development contribute to the continuing frequent occurrence of coronavirus diseases. There is an urgent need for new antiviral strategies to address coronavirus infections effectively. Antiviral drugs are important in the prevention and control of viral diseases. Members of the genus coronavirus are highly similar in life-cycle processes such as viral invasion and replication. These, together with the high degree of similarity in the protein sequences and structures of viruses in the same genus, provide common targets for antiviral drug screening of coronaviruses and have led to important advances in recent years. In this review, we summarize the pathogenic mechanisms of coronavirus, common drugs targeting coronavirus entry into host cells, and common drug targets against coronaviruses based on biosynthesis and on viral assembly and release. We also describe the common targets of antiviral drugs against coronaviruses and the progress of antiviral drug research. Our aim is to provide a theoretical basis for the development of antiviral drugs and to accelerate the development and utilization of commonly used antiviral drugs in China.

Keywords: broad-spectrum; common antivirals; common mechanism; coronavirus; virus targets.

Figure 1

Life cycle of coronavirus and drug targets. The sequence of events, from host cell recognition through the release of the new virion, is represented graphically as steps 1 to 9. The structure of the drug was obtained from PubChem (pubchem.ncbi.nlm.nih.gov).

Figure 2

Common antivirals targeting the coronavirus spike. (A) Side view of the pre-fusion structure of the SARS-CoV-2 spike protein (PDB ID 7WEA) with a single receptor-binding domain in the “up” state. (B) Three pairs of HR1/HR2 of the trimeric S protein (colored green, cyan, and red) form a six-helix bundled coiled-coil structure in the post-fusion state after cleavage at the S1/S2 boundary (PDB ID 6LXT). Arbidol and FD001 inhibit formation of the six-helix bundle (6-HB).

Figure 3

Common antivirals targeting biosynthesis. (A) Types of inhibitors that target PLpro. (B) Superimposed plots of simulations of PEDV 3CLpro (PDB ID 4XFQ, plum), TGEV 3CLpro (PDB ID 1LVO, tan), PDCoV 3CLpro (PDB ID 7KYU, light sky blue), and SADS-CoV 3CLpro (PDB ID 6w81, pale green). The same catalytic sites (His41 and Cys144) are shown in red. (C) Functional domains of RNA helicase (PDB ID 7RDY). One drug−binding pocket is located within the ATP/ADP−binding site where myricetin and scutellarein block the ATP/ADP−binding site. The other is located within the RNA−binding site, where the inhibitor SSYA10−001 blocks the entry of viral ssRNA.

Figure 4

Common antivirals targeting structural proteins. (A) Pentameric oligomerization of transmembrane region (E8-R38) of the SARS-CoV-2 E protein (PDB ID 7K3G), and the co-crystal structure of hexamethylene amiloride with coronavirus envelope protein. (B) Structures of nucleocapsid and its drug-binding pockets (PDB ID 7ACT). The drug-binding pocket of the inhibitor PJ34 (PDB ID 4KXJ) or H3 is located within the interaction interface between the RNA-binding domain and viral single-strand RNA.