The development of Coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020

Abstract

This review fully describes the coronavirus 3CL^pro peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CL^pro inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CL^pro Cys145 residue and thereby achieve irreversible inhibition effects, whereas nonpeptidic small molecule inhibitors mainly interact with residues in the S1', S1, S2 and S4 pockets via hydrogen bonds, hydrophobic bonds and van der Waals forces. Based on the emerging PROTAC technology and the existing 3CL^pro inhibitors, 3CL^pro PROTAC degraders are hypothesised to be next-generation anti-coronavirus drugs.

Keywords: 3C-like protease (3CL(pro)) inhibitors; COVID-19; Coronaviruses; Peptidomimetic inhibitors; Proteolytic targeting chimaera (PROTAC).

Graphical abstract

Fig. 1

Coronavirus (SARS-CoV) genome.

Fig. 2

Simulated superposition of the structures of SARS-CoV-2 3CL^pro (PDB code: 6LU7, blue), SARS-CoV 3CL^pro (PDB code: 1Q2W, red), and MERS-CoV 3CL^pro (PDB code: 4RSP, green). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Peptidomimetic 3CL^pro inhibitors.

Fig. 4

Schematic diagram of the X-ray crystal structure: the interaction of compounds 11 (A) and 12 (B) with SARS-CoV-2 3CL^pro.

Fig. 5

Chemical structures of α-ketoamide inhibitors 24–26. The coloured circles highlight the specific modifications during each development step.

Fig. 6

Novel decahydroisoquinoline derivatives that serve as SARS-CoV 3CL^pro inhibitors.

Fig. 7

Crystal structure of SARS-CoV 3CL^pro superimposed with 29a, 29b and 29c (PDB code: 4TWY).

Fig. 8

Octahydro-isochromene scaffold of SARS 3CL^pro inhibitors.

Fig. 9

38 and its binding pocket with SARS 3CL^pro.

Fig. 10

(A) Primary SAR study of the furyl amide hit compound 39. (B) (R)-40a and (S)-40a.

Fig. 11

X-ray crystal structure of (R)-40a bound to SARS-CoV 3CL^pro (PDB code: 3V3M).

Fig. 12

43 bound to the binding pocket of SARS-CoV 3CL ^pro (PDB code: 4MDS).

Fig. 13

(A) P1 modifications, (B) P2–P1′ exploration and (C) P3 truncation of the hit compound 43.

Fig. 14

Unsymmetrical aromatic disulphides.

Fig. 15

Modelling of 55 with SARS CoV 3CL^pro. The hydrogen bonds between the enzyme and the inhibitor are shown as green dashed lines, and the distances are shown in units of Å. The amino acid residues that contribute to van der Waals contacts with the inhibitor are shown as red arcs. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 16

Design scheme of serine derivatives 64 and 65.

Fig. 17

Evolution of phenyl isoserine derivatives 68a, 68b, and 68c from serine derivatives.

Fig. 18

Structure of pyrazolones and their inhibition of SARS and MERS 3CL^pro.

Fig. 19

Chemical structures of natural product derivatives 76–110.

Fig. 20

Illustration of PROTACs targeting the degradation of 3CL^pro and thereby inhibiting coronavirus assembly and replication.