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Review
. 2020 Apr;25(4):668-688.
doi: 10.1016/j.drudis.2020.01.015. Epub 2020 Jan 30.

Recent discovery and development of inhibitors targeting coronaviruses

Thanigaimalai Pillaiyar  1 , Sangeetha Meenakshisundaram  2 , Manoj Manickam  3
Affiliations
Review

Recent discovery and development of inhibitors targeting coronaviruses

Thanigaimalai Pillaiyar et al. Drug Discov Today. 2020 Apr.

Abstract

Human coronaviruses (CoVs) are enveloped viruses with a positive-sense single-stranded RNA genome. Currently, six human CoVs have been reported including human coronavirus 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and MiddleEast respiratory syndrome (MERS) coronavirus (MERS-CoV). They cause moderate to severe respiratory and intestinal infections in humans. In this review, we focus on recent advances in the research and development of small-molecule anti-human coronavirus therapies targeting different stages of the CoV life cycle.

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Figures

Figure 1
Figure 1
Schematic representation of the taxonomy of Coronaviridae (according to the International Committee on Taxonomy of Viruses). The six human coronaviruses belong to the Alpha- and Beta-coronaviruses genuses, respectively.
Figure 2
Figure 2
(A) Structure of coronavirus and (B) its replication: (Ab: Antibody; DPP4: Dipeptidase Peptidyl 4; TMPRSS2: Transmembrane Protease, Serine 2; PLpro: Papain-like Protease; 3CLpro: 3-C-like Protease; RdRp: RNA dependent and RNA polymerase; nsp: Non-structural protein, ORF: open reading frame, ACE2: Angiotensin converting enzyme, CD13: human aminopeptidase N).Entry targets: (I) Spike protein (RBD, Fusion intermediates); (II) Receptors; a. DPP4/CD26 for MERS, b. ACE2 for SARS and HCoV-NL63, c. 9-O-Acetylated sialic acid for HCoV-OC43 and HCoV-HU1, d. CD13 for HCoV-229E (III) Surface proteases: TMPRSS2. (IV) Endosomal proteases. Polyprotein processing targets: a. Papain-like protease (PLpro), b. 3C-like protease (3CLpro). Replicase targets: a. ADP-ribose-1'-phosphatase (nsp3), b. RNA-dependent and RNA polymerase (nsp12), c. Helicase (nsp13), d.Exonuclease (nsp14), e. Endoribonuclease (nsp15), f. 2'-O-methyltransferase.
Figure 3
Figure 3
Potential anti-viral therapeutics used in patients with SARS and MERS infections.
Figure 4
Figure 4
Drugs repurposed on coronaviruses infections.
Figure 5
Figure 5
Repurposing of various classes of drugs on SARS-and MERS-CoVs.
Figure 6
Figure 6
Overview of SARS and MERS-CoVs polyproteins. (A) Cleavage positions of PLpro and 3CLpro are shown by arrows. B) Cleavage site comparison between SARS and MERS PLpro enzymes (For SARS-PLpro: (L/I)XGG↓(A/D)X and for MERS-PLpro: LXGG↓(A/K)X).
Figure 7
Figure 7
1,2,3-Triazole derivatives (37-42) against coronavirus-229E.
Figure 8
Figure 8
Representative examples of MERS- and/or SARS-CoV PLpro inhibitors (47-54).
Figure 9
Figure 9
Structure of 3CLpro inhibitors that contain Michael acceptor, aldehyde and activated carbonyl functional groups.
Figure 10
Figure 10
Structure of 3CLpro inhibitors (66-74).
Figure 11
Figure 11
Non-peptide SARS-CoV 3CLpro inhibitors contain P2-decahydroisoquinoline, serine and isoserine scaffolds.
Figure 12
Figure 12
Dipeptidyl aldehyde bisulfite adduct inhibitors (84-86), replicase (87) and RNA synthesis inhibitors (88).
Figure 13
Figure 13
Representative host-based anti-Coviral drugs for CoV infections.
Figure 14
Figure 14
Nucleic acid synthesis inhibitors.
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