Potential antivirals and antiviral strategies against SARS coronavirus infections

Abstract

There are a number of antivirals as well as antiviral strategies that could be envisaged to prevent or treat severe acute respiratory syndrome (SARS) (or similar) coronavirus (CoV) infections. Targets for the prophylactic or therapeutic interventions include interaction of the spike (S) glycoprotein (S1 domain) with the host cell receptor, fusion of the S2 domain with the host cell membrane, processing of the replicase polyproteins by the virus-encoded proteases (3C-like cysteine protease [3CLpro] and papain-like cysteine protease) and other virus-encoded enzymes such as the NTPase/helicase and RNA-dependent RNA polymerase. Human monoclonal antibody blocking S1 may play an important role in the immunoprophylaxis of SARS. Fusion inhibitors reminiscent of enfuvirtide in the case of HIV may also be developed for SARS-CoV. Various peptidomimetic and nonpeptidic inhibitors of 3CLpro have been described, the best ones inhibiting SARS-CoV replication with a selectivity index greater than 1000. Human interferons, in particular alpha- and beta-interferon, as well as short interfering RNAs could further be pursued for the control of SARS. Various other compounds, often with an ill-defined mode of action but selectivity indexes up to 100, have been reported to exhibit in vitro activity against SARS-CoV: valinomycin, glycopeptide antibiotics, plant lectins, hesperetin, glycyrrhizin, aurintricarboxylic acid, chloroquine, niclosamide, nelfinavir and calpain inhibitors.

Figure 1.. Genome structure of severe acute respiratory syndrome coronavirus.

Figure 2.. Severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein.

Residue numbers of each region correspond to their positions in the spike protein of SARS-CoV. Six peptides corresponding to the sequences of HR1 and HR2 regions are also shown. Reprinted with permission from [19]. CP: Cytoplasmic domain; HR: Heptad region; SP: Signal peptide; TM: Transmembrane domain.

Figure 3.. Conformational changes of severe acute respiratory syndrome coronavirus spike protein during the process of fusion between the virus and target cell membranes.

Reprinted with permission from [19].

Figure 4.. Calpain inhibitors.

Figure 5.. The severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (Mpro) dimer structure complexed with a substrate–analog hexapeptidyl chloromethyl ketone inhibitor.

(A) The SARS-CoV Mpro dimer structure is presented as ribbons, and inhibitor molecules are shown as ball-and-stick models. Promoter A (the catalytically competent enzyme) is red, promoter B (the inactive enzyme) is blue and the inhibitor molecules are yellow. The N-finger residues of promoter B are green. The molecular surface of the dimer is superimposed. (B) A cartoon diagram illustrating the important role of the N-finger in both dimerization and maintenance of the active form of the enzyme. Reprinted with permission from [27].

Figure 6.. Niclosamide anilide (JMF 1507).

Figure 7.. Phe-Phe dipeptide.

Figure 8.. Cinanserin.

Figure 9.. Bananin.

Figure 10.. Ribbon diagram of the homology model of severe acute respiratory syndrome coronavirus RNA-dependent RNA polymerase with a docked RNA template primer.

α-helices are shown as spirals and β-strands as arrows. The subdomains of the catalytic domain are colored as the N-terminal portion of the fingers subdomain (376–424) in magenta, the base of the fingers (residues 425–584 and 626–679) in blue, palm (residues 585–625 and 680–807) in red, and thumb (residues 808–932) in green. Reprinted with permission from [45].

Figure 11.. Valinomycin.

Figure 12.. Glycyrrhizin.

Figure 13.. Monomeric and polymeric structures of aurintricarboxylic acid, according to [81].

Figure 14.. (A) Mozoribine and ribavirin, (B) chloroquine and (C) niclosamide.