The emergence of SARS-CoV-2 has precipitated an unprecedented effort by the scientific community to find and develop potential therapeutics and vaccines for this new virus to halt the ongoing pandemic’s onslaught. Fortunately, the SARS-CoV-2 genome is highly homologous to SARS-CoV, which caused the SARS outbreak in 2003. Thus, the research on the original SARS virus is potentially applicable to finding a therapeutic for SARS-CoV-2. Small molecules figure prominently in the hunt for therapeutics that can eliminate SARS-CoV-2 or ameliorate the disease’s severity.
SARS-CoV-2 is a single-stranded positive-sense RNA virus. Its genome encodes four structural proteins, spike (S), nucleocapsid (N), membrane (M), and envelope (E), as well as 16 non-structural proteins. Several of these proteins needed for viral transcription and replication are targets for small molecule inhibition and pathways responsible for viral entry into host cells.
The protein 3CLpro (or Mpro) is a cysteine protease that mediates viral replication and transcription via cleavage of viral polyproteins pp1a and pp1ab. Molecules that have been found to inhibit this enzyme include GRL-0496 (Cat# 10-4960), ML300 (Cat# 10-4961), and Ebselen (Cat# 10-2288). 3CLpro is an attractive target as there is no human homolog for this protein.
PLpro is another cysteine protease similar in function to 3CLpro but with the added function of stripping ubiquitin and ISG15 from host-cell proteins to help SARS-CoV evade the immune system. 6-Thioguanine (Cat# 10-1282) and GRL-0617 (Cat# 10-4965) are examples of small molecules targeting this protein.
RNA-dependent RNA polymerase is an important component of the SARS-CoV replication machinery. Researchers have looked at many current and investigational drugs targeting replication for other viruses hoping that they will work against SARS-CoV-2. Remdesivir (and its active metabolite GS-441524 (Cat# 10-4485) has been the most successful of these reagents and is currently being used in the clinic. Favipiravir (Cat# 10-4471) and N4-Hydroxycytidine (EIDD-1931; Cat# 10-3970) have also been shown to have efficacy.
Prevention of viral entry/fusion into host cells is another major area of research. Entry into host cells is typically mediated either by receptor-mediated fusion pathways or ph-dependent endocytic pathways. After binding to ACE2 receptors on the host cell, SARS-CoV-2 uses furin and the serine protease TMPRSS2 to cleave its S-glycoprotein and start the membrane fusion process. The TMPRSS2 inhibitors camostat mesylate (Cat# 10-2196) and nafamostat mesylate (Cat #10-1089) have both displayed significant activity in blocking SARS-CoV-2 infection. Umifenovir (Arbidol; Cat# 10-4472) has been shown to inhibit SARS-CoV-2 infection by blocking virus entry as well as release from endolysosomes during intracellular trafficking. E-64d (Cat# 10-1347) is another cysteine protease inhibitor that blocks S-glycoprotein cleavage. The oft-cited lysosomotropic agents chloroquine and hydroxychloroquine increase lysosomal pH interfering with the endosomal viral entry pathway. Omeprazole (Cat# 10-2822) is an inhibitor of H+,K+-ATPase that also interferes with lysosomal pH. It also increases remdesivir activity by a factor of 10.
Many other small molecules have activity against SARS-CoV-2 through a variety of mechanisms. These include Emetine (Cat# 10-3001), Ivermectin (Cat#10-2628), Nitazoxanide (Cat# 10-4633), Amiodarone (Cat# 10-2468), Siramesine (Cat# 10-4202), Astemizole (Cat# 10-1064), MK-2206 (Cat #10-4801), MDL-28170 (Cat# 10-3005), Nelfinavir mesylate (Cat# 10-3050), PB-28 (Cat# 10-4665), Boceprevir (Cat# 10-5087), in addition to many other Focus products.
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