Insights into SARS-CoV-2: Small-Molecule Hybrids for COVID-19 Treatment

Abstract

The advantages of a treatment modality that combines two or more therapeutic agents with different mechanisms of action encourage the study of hybrid functional compounds for pharmacological applications. Molecular hybridization, resulting from a covalent combination of two or more pharmacophore units, has emerged as a promising approach to overcome several issues and has also been explored for the design of new drugs for COVID-19 treatment. In this review, we presented an overview of small-molecule hybrids from both natural products and synthetic sources reported in the literature to date with potential antiviral anti-SARS-CoV-2 activity.

Keywords: COVID-19; SARS-CoV-2 Mpro; antiviral activity; drug design; molecular hybridization; natural product hybrids; small molecules.

Figure 1

Design strategy for hybrid compounds.

Figure 2

Schematic representation of the genome organization and functional domains for SARS-CoV-2. The single-stranded RNA genome of SARS-CoVs has two large genes, the ORF1a and ORF1b genes, which encode 16 non-structural proteins (nsp1–nsp16) that are highly conserved throughout coronaviruses. The structural genes encode the structural proteins, spike glycoprotein (S), envelope (E), membrane (M) and nucleocapsid (N), which are common features of all coronaviruses. Polyproteins pp1a and pp1ab embed 11 and 16 non-structural proteins (Nsps), respectively; the green and pink triangles indicate the cleavage sites of the protease PL^pro and M^pro, respectively. Fifteen sites where polyproteins pp1a and pp1ab are cut by proteases are represented with arrows. PL^pro cleaves at three distinct sites while M^pro cleaves at twelve distinct sites, including those for RNA-dependent RNA polymerase (RdRp) encoded by nsp12 and Helicase (Hel) encoded by nsp13.

Figure 3

Schematic representation of virus infection and replication mechanism in host cell.

Figure 4

ACE2 viral-induced dysregulation and inflammatory signaling in host cell.

Figure 5

Artemisinin-derived hybrids and selected biological data. (A): molecular structures of artemisinins; (B): dihydroatemisinin–thymoquinone hybrids; (C): molecular structures of dihydroatemisinin–quinoline hybrids; (D): molecular structures of dihydroatemisinin–ursodeoxycholic bile acid hybrids.

Figure 6

Peptidomimetic-based hybrids: molecular structures of starting frameworks; molecular structures of hybrids and selected biological data.

Figure 7

Molecular structures of 1,2,3-triazole-based hybrids and selected biological data.

Figure 8

Chemical structure of benzothiazolyl–pyridine, benzothiazolyl–coumarin, thiouracil–coumarin, thiazole–pyrazole hybrids and selected biological data.

Figure 9

Chemical structure of hybrids and selected biological data.

Figure 10

Chemical structure of hybrids and selected biological data.