Note: The products listed in this article are for biomedical research only. They are not for human or veterinary use.

Currently, there are no approved drugs to treat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that causes coronavirus disease 2019 (COVID-19). Existing FDA-approved drugs that have a known favorable safety profile are being examined for strategies to treat the disease and fast-track a treatment plan. The influenza drug favilavir (favipiravir; sold for research use only under the name T-705) has just been approved as an investigational therapy, and the Ebola virus drug remdesivir is currently undergoing clinical trial in coronavirus patients in China. The rational selection of drugs already on the market is being made based on their ability to inhibit any proteins essential for virus-receptor interaction and/or viral life cycle.

SARS-CoV-2, formerly known as the 2019 novel coronavirus (2019-nCoV), is a positive-sense, single-stranded RNA virus. This virus shares 79.5% sequence identity with SARS-CoV and uses the same angiotensin converting enzyme 2 (ACE2) receptor as SARS-CoV as a mechanism of cell entry. ACE2 is highly concentrated in airway epithelial cells. An envelope-anchored spike protein mediates coronavirus entry into host cells by binding to the host ACE2 receptor and then fusing viral and host membranes. Coronaviruses, including SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes, depending on the cell or tissue type. This virus-receptor interaction facilitates both cross-species and human-to-human transmission of the virus, allowing the viral genome to be delivered to the host cell cytoplasm for replication.

Virus-Host Fusion Inhibitors

The broad-spectrum antiviral arbidol blocks viral fusion with target membranes, prohibiting viral entry into cells. Because it targets a common critical step for viral replication, it is effective against numerous viruses, including influenza A, B, and C as well as hepatitis B and C. A study has revealed that arbidol can effectively inhibit SARS-CoV-2 infection at a concentration of 10-30 µM in vitro. Besides its antiviral action, arbidol has been reported to produce an immunomodulatory response by inducing interferon production and stimulating the phagocytic function of macrophages.

Blocking virus-host fusion through inhibiting the Abl kinase pathway is also a promising target for the development of antiviral therapies, since this kinase activity is required for entry of coronaviruses. Abl kinases are composed of distinct domains that enable them to act as scaffolds for signaling complexes and to regulate protein function through phosphorylation of downstream targets. Pathogens have been shown to exploit Abl kinase signaling to rearrange F-actin cytoskeleton and trigger phosphorylation of viral effector proteins to facilitate viral-host fusion. A high-throughput screen identified imatinib as an inhibitor of SARS-CoV and MERS-CoV. It is likely that inhibition of Abl interferes with the actin dynamics required for virus-host fusion. Cayman offers several Abl kinase inhibitors that can be used to study the coronavirus membrane fusion step.

Abl Kinase Inhibitors

Imatinib (mesylate)

Saracatinib

GNF-2

GNF-5

See all Abl family & Bcr-Abl inhibitors

In addition to the coronavirus entering the host by binding to the host cell’s ACE2 receptor, participation of ACE in the renin-angiotensin system has been implicated in the acute, accelerated lung fibrosis associated with coronavirus infection. ACE mediates the conversion of angiotensin I to angiotensin II, which interacts with angiotensin II type 1 (AT₁) receptors. In some pathological conditions, overactivation of AT₁ receptors may lead to damaging events like fibrosis in the liver and lungs, possibly through increasing TGF-β expression. Presumably, a drug that would inhibit ACE, such as lisinopril, or block AT₁, like losartan, would have a beneficial effect of mitigating the heavy fibrosis associated with acute cases of SARS infections by shutting down the ACE-angiotensin II-AT₁ pathway. ACE inhibitors may further play a role in disallowing viral fusion of the coronavirus to the host cell and entry into the cell, denying its pathway to replication.

See all ACE inhibitors

See all AT₁ receptor antagonists

Protease Inhibitors

After infection, genomic RNA is released into the cytoplasm of the host cell and translated into two long, overlapping polyproteins, pp1a and pp1ab, which are processed by two proteases, the main protease (M^pro or 3C-like protease) and the papain-like protease (PL^pro). The hydrolytic activity of these proteases produces multiple functional proteins that are essential to forming the replicase complex for viral replication. Protease inhibitors block the viral life cycle by selectively preventing such proteolytic cleavage. The protein sequences of SARS-CoV M^pro and SARS-CoV-2 M^pro are 96% identical, indicating that protease inhibitors that have shown success against SARS-CoV should have similar efficacy against SARS-CoV-2. Both mycophenolic acid and the hepatitis C virus (HCV) protease inhibitors telaprevir, boceprevir, and grazoprevir have all been shown to bind to the active site of SARS-CoV-2 PL^pro and hence, may be useful in preventing viral replication. A molecular docking study also revealed the HIV protease inhibitor indinavir to nearly perfectly overlap the region of the protein pocket of M^pro. Some success has already been shown in treating SARS-CoV-2-infected patients with the HIV protease inhibitors lopinavir and ritonavir in combination with the influenza neuraminidase inhibitor oseltamivir. However, a clinical study aimed to compare arbidol and lopinavir/ritonavir treatment for patients with COVID-19 with lopinavir/ritonavir only, supported lopinavir/ritonavir therapy but not lopinavir/ritonavir plus arbidol therapy. Cayman offers several protease inhibitors that can be used in candidate screens for inhibitors of M^pro and PL^pro activity.

See all protease inhibitors

RNA-Dependent RNA Polymerase Inhibitors

Once inside the host cytoplasm, the single-stranded RNA virus serves as an RNA template that is replicated into complementary strands through the action of the RNA-dependent RNA polymerase (RdRp). The initiation step of RNA synthesis involves the addition of a nucleoside triphosphate to the 3’ end. The strand is elongated by repeated nucleotidyl transfer reactions with subsequent nucleoside triphosphates added to generate the complementary RNA. A class of nucleotide analogs have been developed as antiviral drugs to confuse RdRp as they are incorporated into RNA strands and induce non-obligate RNA chain termination. During the 2003 SARS outbreak, the RdRp inhibitor ribavirin in combination with the HIV protease inhibitors lopinavir and ritonavir was shown to reduce the disease course of clinical trial patients. BCX4430 (galidesivir) is in an advanced development stage under the FDA Animal Efficacy Rule to counteract viral threats from coronaviruses, flaviviruses, filoviruses, paramyxoviruses, togaviruses, bunyaviruses, and arenaviruses.

Development of some nucleoside-based therapeutics for SARS-CoV infections has been hampered by their removal via a proofreading 3’-5’ exoribonuclease (ExoN), but Remdesivir, an adenosine nucleoside analog that demonstrates broad-spectrum anti-RdRp activities has been shown to evade ExoN surveillance. Remdesivir was originally developed to treat Ebola virus, but also shows promising efficacy against SARS-CoV and MERS-CoV in pilot studies with an excellent safety profile in clinical trials so far. Remdesivir was used to treat the first US patient infected with SARS-CoV-2, who recovered. It is in phase 3 trials in Wuhan patients infected with SARS-CoV-2, overseen by the China-Japan Friendship Hospital in Beijing (NCT04252664 and NCT04257656). Remdesivir is a prodrug that metabolizes into its active form GS-441524. Cayman offers the following RdRp-targeted drugs that can be used to study viral replication.

RdRp Inhibitors

BCX4430 (Galidesivir)

GS-441524

Remdesivir

Ribavirin

T-705 (Favipiravir)

See all RdRp Inhibitors

Oxysterol-Binding Protein Inhibitors

During viral replication, oxysterol-binding protein (OSBP) plays a vital role in producing the membrane-bound viral replication organelles that form at the membrane contact sites between the ER and Golgi. The antifungal drug itraconazole and the natural compound OSW-1, which is being investigated as an anticancer drug, have been identified as functioning through targeting OSBP. While the binding modality of itraconazole is not known, OSW-1 has been shown to affect binding to one of the two established OSBP ligand binding sites. OSW-1 induces a prolonged reduction of cellular OSBP levels and has been shown to inhibit enterovirus replication. Coronaviruses may also be a suitable target for OSBP-targeted compounds.

Oxysterol-binding Protein Inhibitor

Itraconazole

OSW-1

Endosomal pH Regulators

Viruses entering host cells by endocytosis require an acidic pH in endosomal vesicles for virus-host fusion and to carry out the replication process. The antimalarial agent chloroquine (phosphate) is a weak base that shows broad-spectrum antiviral activities by increasing the endosomal pH required for viral activity. It can impair the replication of viruses by interfering with endosome-mediated viral entry as well as the late stages of replication of enveloped viruses whose glycosylation step requires a low pH for enzyme processing. Chloroquine (phosphate) can also suppress the release of TNFα and interleukin 6, which contribute to inflammatory complications of viral diseases. In multicenter clinical trials conducted in China, chloroquine (phosphate) has demonstrated potent efficacy in treating pneumonia associated with COVID-19.

Endosomal Acidification Inhibitors

Chloroquine (phosphate)

Hydroxychloroquine (sulfate)

Conclusion

Various potential targets for development of COVID-19 therapeutics exist along the stages from when a positive-sense, single-stranded RNA virus infects host cells and replicates. With little time available for drug testing and development, the repurposing of approved pharmaceutical drugs provides the most immediate solution for addressing the COVID-19 outbreak. Indeed, knowledge gained from the previous SARS outbreak has placed researchers in an advantageous position of better understanding solutions of how to address long-term treatment of this newly identified coronavirus. With hundreds of antiviral compounds in our catalog and custom synthesis services at the ready, Cayman scientists are poised to support the development of an effective therapeutic strategy against SARS-CoV-2 infection.

Further Reading: Uncovering the Role of BRD2 in COVID-19
 

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• Includes a variety of compounds with antiviral activity against HIV, hepatitis B virus, hepatitis C virus, influenza, herpes simplex virus, and coronaviruses, among others

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