Drugs Repurposed against SARS CoV-2 Drug Targets

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1		Ankita Khataniar	--	1814	2023-07-13 11:15:51	\|
2	layout	Jessie Wu	Meta information modification	1814	2023-07-14 03:48:35	\|

This entry is adapted from the peer-reviewed paper 10.3390/covid2020011

Drug repurposing is a process to identify new roles for existing drugs and is generally considered an efficient and economical approach. Repurposing—also known as re-profiling, re-tasking, repositioning, and rescue of drugs—can help identify new therapies for diseases, at a lower cost and in a shorter time.

drug repurposing COVID-19

1. Introduction

The discovery and licensed use of a drug come with a long gestation period. The development of a drug for any disease, especially for diseases caused by viruses, takes time, even in an accelerated mode; it would take around 3–5 years to market it as a ready-to-use product. The cost of the new drug development process amounts to more than a billion dollars, extending for 10–15 years with a success rate of only 2.01% ^[1]. This creates a lag in the productivity of pharmaceutical research to develop a new drug, resulting in a persistent gap between therapeutic needs and available treatments. Despite base evidence being of variable quality, existing drugs have been repurposed in the war against the coronavirus pandemic ^[2]. Even though vaccines have been made available for the general populace, there is no specific treatment for the patients suffering from the disease. Thus, investigational molecules that fail to show efficacy for a predetermined medication typically provide alternative therapeutic effects for another disease ^[1]. With computational tools and improving knowledge of virology and clinical presentation of COVID-19, researchers are tapping into a broadening pool of potential pharmacological targets.

Currently, several groups of drugs are being investigated against COVID-19. This includes hydroxychloroquine, remdesivir, chloroquine, lopinavir, ritonavir, and so on. These are established drugs used for the treatment of SARS-CoV, MERS-CoV, and other viruses. As there is an emergency requirement to establish potential inhibitors against COVID-19, repurposing drugs is an ideal strategy to gain headway into the same. During repurposing, virtual screening, pharmacophore modelling, other computational methods, and experimental methods are extensively used. As an example of successful stances in drug repurposing, one need not look any further than the treatment modules for the Zika virus, a mosquito-borne flavivirus. Zika virus infection lacks a specific drug or vaccine for its treatment. Over the years, researchers around the globe have screened thousands of previously studied compounds and have identified several compounds with anti-ZIKV activities. Barrows and colleagues identified approximately 24 potential drugs with anti-ZIKV activities from a library of 774 FDA-approved drugs. Based on such studies, niclosamide and azithromycin are the most commonly used drugs in ZIKV treatment, especially for pregnant women. Chloroquine, a commonly used anti-inflammatory and antimalarial drug, is also used to treat the same ^[1].

The methodologies adopted in drug repurposing can be divided into three broad groups depending on the pharmacological, toxicological, and biological activity information available. These are drug-oriented, target-oriented, and disease/therapy-oriented ^[1].

2. Drugs Repurposed against COVID-19 Drug Targets

Drug repositioning is not only a current scientific trend but spans across several decades. Drugs with a specific clinical indication have been further tested to discover alternative clinical indications for different diseases. The most common drug repurposing examples are NSAIDs (anti-inflammatory drugs) being used as anticancer agents. Chloroquine, an antimalarial drug, and azithromycin, an antibacterial antibiotic are under development as antiviral drugs against COVID-19 ^[3]. Drugs currently being tested for repositioning in COVID-19 can be distinguished as drugs potentially able to inhibit one or more steps of the coronavirus lifecycle and those that can counteract the effects of SARS-CoV-2 infection, such as the amplified immune response and the massive cytokine release, both of which lead to severe complications such as coagulopathy and acute respiratory distress syndrome (ARDS). The first is remdesivir, first developed in 2009 to treat hepatitis C, then repurposed to treat Ebola. Although ineffective in treating both diseases, later animal studies found that it effectively managed other coronaviruses such as SARS and MERS. It has proven effective in shortening recovery time from COVID-19 in some patients if administered early. However, it is to be used with only the most severely affected patients in critical care units. Another group of drugs that have previously been widely used among critically ill patients with SARS and MERS are glucocorticoids, powerful anti-inflammatory drugs that inhibit the production and survival of T-cells and macrophages. Although controversial, glucocorticoids have been used to treat patients critically ill with COVID-19 ^[4]^[5]. A comprehensive list of repurposed drugs used against drug targets of SARS-CoV2 is provided in Table 1.

Table 1. A list of drugs that are being repurposed as viable treatment options against drug targets of SARS-CoV2.

Targets	PDB ID	Repurposed Drugs	References
Envelope (E) protein	7K3G	Ascorbyl palmitate, cinametic acid, lauric acid, guaifenesin, nabumetone, nafcillin, octacosanol, palmidrol, and salmeterol	^[5]
Main protease (Mpro).	7C2Q	Dipyridamole, candesartan cilexetil, candesartan, oxytetracycline, valganciclovir hydrochloride, roxatidine acetate, omeprazole, sulfacetamide, cimetidine, disulfiram, atazanavir, hydroxychloroquine, chloroquine, indinavir montelukast sodium, and maribavir	^[6]
Membrane (M) protein	3I6G	Colchicine, remdesivir, bafilomycin A1, temozolomide, and colchicine derivatives	^[7]
Nucleocapsid (N) protein	6M3M	Apamycin, camostat, nafamostat, saracatinib, trametinib, cefuroxime, ceftriaxone, cefotaxime	^[8]
RNA-dependent RNA polymerase (RdRp)	7D4F	molnupiravir, grazoprevir, ganciclovir, atazanavir, daclatasvir, acyclovir, etravirine, entecavir, efavirenz, asunaprevir, abacavir dolutegravir, lomibuvir, penciclovir, trifluridine, danoprevir, ritonavir, saquinavir, raltegravir, and lamivudine	^[9]
S-protein	6VXX	Pemirolast, isoniazid pyruvate, nitrofurantoin, and eriodictyol	^[10]

2.1. Nafcillin

Nafcillin is a semi-synthetic, narrow-spectrum antibiotic, a beta lactamase-resistant penicillin. The bactericidal action of penicillin inhibits cell wall synthesis due to the presence of the beta-lactam ring. However, certain bacteria develop resistance against the beta-lactam ring by synthesizing beta-lactam inhibitors (i.e., beta-lactamase or penicillinase). Penicillinase resistance drugs were introduced to combat this resistance ^[11]. Currently, nafcillin is being used to treat penicillinase-producing staphylococcal species, particularly methicillin-sensitive Staphylococcus aureus (MSSA). Nafcillin is also being used to treat non-specific lower respiratory tract infections and community-acquired pneumonia (CAP) ^[12]. Nafcillin is not known to cause life-threatening adverse side effects. An analysis by Das et al. shows the highest binding affinity with the TMD domain of monomeric E-protein ^[5]. Thus, nafcillin can be considered for redirecting its purpose for the treatment of SARS-CoV-2 infection as it could also combat bacterial co-infection in a COVID patient, which produces the same symptoms as seen in SARS-CoV-2 infection.

2.2. Nabumetone

Nabumetone is an FDA-approved non-selective anti-inflammatory drug (NSAID) that is currently being used for its anti-inflammatory and antipyretic effects. It is a prodrug that goes through biotransformation within the liver to produce the active component, 6-methoxy-2-naphthyl acetic acid (6MNA), that inhibits the synthesis of prostaglandins by acting on cyclooxygenase (COX) I and II. Prostaglandins are responsible for initiating fever by signaling the hypothalamus to increase body temperature. Prostaglandin acts as an inflammatory mediator acting on blood vessels to promote an inflammatory response. NSAIDs mediate anti-inflammatory effects by preventing vasodilation, reducing capillary permeability and cytokine release from endothelial cells. Altogether, these effects impede the migration of immunocompetent cells to the injury site, thereby preventing uncontrolled immune system activation and inflammation ^[12].

2.3. Octacosanol

Octacosanol is the main component of plant-extracted natural wax and is a low-molecular-weight primary aliphatic alcohol. Its role is mainly investigated for the treatment of Parkinson’s disease. It is approved as a nutraceutical by the FDA and is marketed as the main component of policosanol (PC), a generic term for a natural mixture of primary alcohols isolated originally from sugarcane wax.

2.4. Cinametic Acid

Cinametic acid is an FDA-approved food additive, mainly obtained from oil of cinnamon and other plant sources. Among the many therapeutic functions of cinnamic acid, one of its roles has also been linked to inhibiting angiotensin-converting enzyme (ACE). ACE converts angiotensin (Ang) I to Ang II. Ang II is responsible for constricting blood vessels and increasing blood pressure or hypertension, one of the risk factors for COVID-19, via binding to angiotensin1 receptor (AT1R) and activating a cascade of signaling pathways. The role of cinametic acid in inhibiting ACE will hamper conversion of Ang I to Ang II, which can reduce hypertension. Further, Ang II gets converted to Ang-(I-VII) by ACE2 in the absence of ACE.

2.5. Ascorbyl Palmitate

Ascorbyl palmitate is an FDA-approved small molecule. Mainly, it is a fat-soluble form of vitamin C formed by the ester of ascorbic acid and palmitic acid. Being an amphipathic molecule, it has the advantage of being more stable and easily enters into cell membranes.

2.6. Guaifenesin

Guaifenesin is an FDA-approved over-the-counter (OTC) or non-prescription expectorant for treatment of cough and the common cold. It aids in the clearance of mucous and other respiratory tract secretion by increasing the volume of trachea and bronchi and reducing mucus viscosity, otherwise leading to congestion, chronic bronchitis, and COPD, commonly seen in ARDS. As a result of this, the action of guaifenesin results in a more productive cough, thus combating the condition of ARDS. This is also expected to happen if administered to COVID-19 patients as it can potentially disrupt the formation of the pentameric structure of E-protein, which causes ARD ^[5].

2.7. Remdesivir

Remdesivir, a nucleoside analogue prodrug, was developed for use against the Ebola virus, is currently under trial at many medical institutions, and is known to be effective against MERS-CoV. It has demonstrated a better safety profile than other drugs in treating acute Ebola viral infections. It gets activated into triphosphate, inhibits viral RNA polymerase, and has manifested in vitro and in vivo activity against MERS-CoV and SARS-CoV-2. It effectively treated a severe patient with severe pneumonia who needed mechanical ventilation but not inotropic agents for support of circulation. Findings have been mixed in studies being conducted regarding the efficacy of remdesivir for COVID-19 treatment. A multinational cohort research supported by Gilead Sciences showed clinical improvement for 68% of severe COVID-19 patients treated with compassionate use of remdesivir ^[13].

2.8. Molnupiravir

Molnupiravir is an isopropyl ester prodrug, which initially emerged as a possible treatment of influenza viruses, and encephalitic alphaviruses such as Venezuelan, Eastern, and Western equine encephalitic viruses. It is derived from the ribonucleoside analog β-D-N4-hydroxycytidine (NHC) triphosphate that converts to its active form molnupiravir (MTP) in the cell. This drug appears to work by the mechanism of “error catastrophe”; this is essentially the concept that by increasing the rate of mutation in the viral genome beyond a biologically tolerable threshold, the virus will no longer be able to exist. It is a broad-spectrum antiviral drug with a two-step mutagenesis mechanism. It targets the virally encoded RdRp of the SARS-CoV-2 and competitively inhibits the cytidine and uridine triphosphates and incorporates MTP. The RdRp utilizes the NHC triphosphate to incorporate either A or G in the active centers. This, in turn, helps in escaping proofreading of a mutated RNA. The resulting mutagenesis is lethal to the virus ^[14].

2.9. Nirmatrelvir

Nirmatrelvir is an irreversible inhibitor of SARS-CoV-2 drug target Mpro. It is co-formulated with ritonavir, allowing an oral route of administration (known as Paxlovid). When treatment is initiated during the first days after symptom onset, it results in roughly 90% protection against severe COVID-19 patients ^[15].

2.10. Ganciclovir

Ganciclovir, originally used to treat cytomegalovirus (CMV) infection, has shown effectiveness in a research for COVID-19 treatment at 0.25 g intravenously every 12 h. Several other studies have also found such antiviral drugs to reduce viral load and avert possible respiratory impediments ^[16].

References

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Rudrapal, M.; Khairnar, J.; Jadhav, G. Drug repurposing (DR): An emerging approach in drug discovery. In Drug Repurposing Hypothesis, Molecular Aspects and Therapeutic Applications; IntechOpen: London, UK, 2020.
Balaji Hange, V. A Narrative Literature Review of Global Pandemic Novel Coronavirus Disease 2019 (COVID-19): Epidemiology, Virology, WŽłĞnθĂů Drug Treatments Available. Arch. Med. 2020, 12, 1–9.
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