Drug Development and Medicinal Chemistry Efforts toward SARS-Coronavirus and Covid-19 Therapeutics

Abstract

The COVID-19 pandemic caused by SARS-CoV-2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID-19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell-surface receptors, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA-dependent RNA polymerase for RNA replication. There has been a lot of ground work for drug discovery and development against these targets. Also, high-throughput screening efforts have led to the identification of diverse lead structures, including natural product-derived molecules. This review highlights past and present drug discovery and medicinal-chemistry approaches against SARS-CoV, MERS-CoV and COVID-19 targets. The review hopes to stimulate further research and will be a useful guide to the development of effective therapies against COVID-19 and other pathogenic coronaviruses.

Keywords: Covid-19; SARS-CoV; coronavirus; drug discovery; protease inhibitors.

Figure 1

Genome organization of SARS‐CoV‐2, highlighting open reading frames (ORF 1a and ORF 1b) nonstructural, structural and accessory proteins along with both proteases and their corresponding cleavage sites. The 16 nsps are numbered and are shown shaded in gray with the exceptions of PLpro (blue) and 3CLpro (red). The structural and accessory proteins are shown and individual ribbon diagrams for each protease are also shown in individually colored boxes PLpro (blue dashed box) and 3CLpro (red dashed box). The PDB codes for 3CLpro and PLpro from SARS‐CoV‐2 (COVID‐19) are also shown.

Figure 2

Structure of compounds 1 and 2.

Figure 3

Structure of SARS‐CoV 3CLpro inhibitors 3–5.

Figure 4

X‐ray crystal structure of compound 4 in the SARS‐CoV 3CLpro active site (PDB ID: 2ALV).

Figure 5

X‐ray crystal structure of compound 5 in the SARS‐CoV 3CLpro active site (PDB ID: 2QIQ).

Figure 6

Structure of SARS‐CoV 3CLpro inhibitors 6–11.

Figure 7

Structure of broad‐spectrum inhibitors 12–15.

Figure 8

X‐ray crystal structure of compound 13 in the SARS‐CoV 3CLpro active site (PDB ID: 5N19).

Figure 9

Structure of α‐ketoamide SARS‐CoV‐2 3CLpro inhibitors 16 and 17.

Figure 10

Structure of SARS‐CoV 3CLpro inhibitors 18 and 19.

Figure 11

X‐ray crystal structure of compound 18 in the SARS‐CoV 3CLpro active site (PDB ID: 2A5K).

Figure 12

Benzotriazole esters 20–23 as covalent SARS‐CoV 3CLpro inhibitors.

Figure 13

Halopyridinyl esters 24–27 as covalent SARS‐CoV 3CLpro inhibitors.

Figure 14

Covalent indole‐based SARS‐CoV 3CLpro inhibitors 28–33.

Figure 15

Structure of noncovalent SARS‐CoV 3CLpro inhibitors 34–37.

Figure 16

Structure of noncovalent SARS‐CoV 3CLpro inhibitors 38–41.

Figure 17

Structure of noncovalent SARS‐CoV 3CLpro inhibitors 42–45.

Figure 18

X‐ray crystal structure of compound 45 in the SARS‐CoV 3CLpro active site (PDB ID: 3ATW).

Figure 19

Design of decahydroisoquinolyl‐based scaffold for 3CLpro inhibitors.

Figure 20

Decahydroisoquinolyl‐based SARS‐CoV 3CL pro inhibitors 46–49.

Figure 21

X‐ray crystal structure of compound 46 in the SARS‐CoV 3CLpro active site (PDB ID: 4TWW).

Figure 22

Octahydroisochromene‐based SARS‐CoV 3CLpro inhibitors 50–53.

Figure 23

Structures of SARS‐CoV 3CLpro inhibitors 54–56.

Figure 24

Structures of isatin‐based SARS‐CoV 3CLpro inhibitors 57–60.

Figure 25

Structures of SARS‐CoV 3CLpro inhibitors 61 and 62.

Figure 26

Structures of pyrazolone‐ and dihydropyrimidine‐based SARS‐CoV 3CLpro inhibitors 63–68.

Figure 27

SARS‐CoV 3CLpro inhibitors 69–73 derived from screening activities.

Figure 28

SARS‐CoV 3CLpro inhibitors 74–78 derived from screening activities.

Figure 29

SARS‐CoV 3CLpro inhibitors 79–84 derived from natural sources.

Figure 30

Hit compound 85 and optimized derivatives 86 and 87.

Figure 31

X‐ray crystal structure of compound 86 in the SARS‐CoV 3CLpro active site (PDB ID: 3 V3 M).

Figure 32

Structures of optimized SARS‐CoV 3CLpro inhibitors 88–91.

Figure 33

Hit compound 92 and optimized derivatives 93 and 94.

Figure 34

X‐ray crystal structure of compound 92 in the SARS‐CoV 3CLpro active site (PDB ID: 4MDS).

Figure 35

Structures of optimized SARS‐CoV 3CLpro inhibitors 95–98.

Figure 36

Hit compound 99 and optimized derivative 100.

Figure 37

X‐ray crystal structure of compound 100 in the SARS‐CoV PLpro active site (PDB ID: 3E9S)

Figure 38

Structures of PLpro inhibitors 101–106.

Figure 39

Hit compound 107 and optimized derivative 108.

Figure 40

X‐ray crystal structure of compound 108 in the SARS‐CoV PLpro active site (PDB ID: 3MJ5).

Figure 41

Structures of PLpro inhibitors 109–112.

Figure 42

Structures of PLpro inhibitors 113–116.

Figure 43

X‐ray crystal structure of compound 115 in the SARS‐CoV PLpro active site (PDB ID: 4OW0).

Figure 44

SARS‐CoV and MERS‐CoV PLpro inhibitors 117–123.

Figure 45

Viral entry inhibitors 124–127.

Figure 46

Viral entry inhibitors 128–132.

Figure 47

RdRp inhibitors 133–136.

Figure 48

Structure of chloroquine (137), hydroxychloroquine (138) and compound 139.