European Review for Medical and Pharmacological Sciences 2021; 25: 4163-4173 Antiviral drugs proposed for COVID-19: action mechanism and pharmacological data F. ROMMASI1, M.J. NASIRI2, M. MIRSAIEDI3 1Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran 2Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran 3Division of Pulmonary and Critical Care, University of Miami, Miami, FL, USA Abstract. – OBJECTIVE: As a beta-coronavi- Key Words: rus, Coronavirus disease-2019 (COVID-19) has COVID-19, Pharmacology, Coronaviruses, Antiviral caused one of the most significant historical drugs, Viral replication. pandemics, as well as various health and med- ical challenges. Our purpose in this report is to collect, summarize, and articulate all essential information about antiviral drugs that may or Abbreviations may not be efficient for treating COVID-19. Clin- ical evidence about these drugs and their pos- WHO = World Health Organization; SARS-CoV-2 = Se- sible mechanisms of action are also discussed. vere acute respiratory syndrome coronavirus 2; SARS = MATERIALS AND METHODS: To conduct a Severe acute respiratory syndrome; MERS = Middle comprehensive review, different keywords in var- East(ern) Respiratory Syndrome; RNA =Ribonucleic ac- ious databases, including Web of Science, Sco- id; S(P) = Spike protein; Kb = Kilo base pairs; HE = pus, Medline, PubMed, and Google Scholar, were Hemagglutinin esterase; ACE 2 = Angiotensin-converting pro Pro searched relevant articles, especially the most re- enzyme-2; 3CL = 3-chymotrypsin-like protease; PL cent ones, were selected and studied. These se- = Papain-like protease; ACEi = Angiotensin-convert- lected original research articles, review papers, ing-enzyme inhibitors; ADR = Acute respiratory dis- tress syndrome; C = Maximum concentration; RdRp = systematic reviews, and even letters to the editors m were then carefully reviewed for data collection. RNA-dependent RNA-polymerase; DCGI = Drug Con- RESULTS: SARS-CoV-2 is the newest mem- troller General of India; AIDS = Acquired immunode- ber of the coronavirus family, and there are still ficiency syndrome; US FDA = United States Food and no promising therapies or particular antiviral Drug Administration; HA = Hemagglutinin; SPs = Spike compounds to fight it. After entering the body, proteins; HCV = Hepatitis C virus; ER = Endoplasmic SARS-CoV-2 penetrates the cells by attaching reticulum. to specific lung cell receptors, called angioten- sin-converting enzyme-2. Then, by employing cell division machinery, it replicates through Introduction a complex mechanism and spreads through- out the patient’s body. Various antiviral drugs, The new coronavirus disease, introduced by including anti-influenza/HIV/HCV drugs, have the World Health Organization (WHO) on Feb- been applied for treating COVID-19 patients. Due to the similarity of the structure and tran- ruary 11, 2020, as Coronavirus Disease-2019 scriptional mechanism of COVID-19 to a number (COVID-19, formerly 2019-nCoV), is the latest of viruses, some of the listed drugs have been health-medical challenge in the world. This novel beneficial against SARS-CoV-2. However, the ef- coronavirus is named Severe Acute Respiratory fectiveness of others is in an aura of ambiguity Syndrome Coronavirus 2019 (SARS-CoV-2) by and doubt. the International Virus Classification Commis- CONCLUSIONS: Some of the antiviral medi- sion1. The first case of COVID-19 was identified cations listed and discussed in this article have in Wuhan, Hubei Province, China, and has since been effective in the treatment of COVID-19 pa- tients or preventing the virus from spreading spread to almost all countries. On January 30, further. However, other drugs have to be investi- 2020, the WHO convened a meeting to introduce gated to reach a reliable conclusion about their the pandemic as an international health emergen- effectiveness or ineffectiveness. cy2. However, the prevalence of coronaviruses in Corresponding Authors: Mohammad Javad Nasiri, Ph.D, MPH; e-mail: [email protected] Foad Rommasi, B.sc.; e-mail: [email protected] 4163 F. Rommasi, M.J. Nasiri, M. Mirsaiedi the world has not been unprecedented. In the last SARS-CoV-2 is a beta coronavirus, and its ge- two decades, SARS and Middle East Respiratory nome length is about 26-32 Kilo base pairs (kb). Syndrome (MERS), respectively in 2003 and The genetic material of this virus is bound to 2014, have been epidemics of coronavirus3. The nucleocapsid proteins, and the envelope protein reproduction number of the 2019-nCoV is esti- structures surround it. Structural proteins, in- mated between 2 and 3, while its fatality rate is cluding spike proteins (SP), protein membranes predicted around 0.5-1.5%4. The most significant (M), small membrane protein (SM), and another symptoms in COVID-19 patients are fever, dry membrane glycoprotein called hemagglutinin cough, loss of sense of taste, lethargy, and short- esterase (HE), are encoded by the viral RNA10,11. ness of breath5. Anosmia is also one of the most The schematic structure of 2019-nCoV is illus- critical symptoms in recent COVID-19 patients6. trated in Figure 1. It is stated that COVID-19 is more contagious When SARS-CoV-2 enters the body and than other coronaviruses, and its transmission comes in contact with the host cell membrane, rate is higher than the closely related strain, some changes occur in the structure of the virus. SARS-CoV-10 7. There are some similarities be- The human TMPRSS2 protein alters the confor- tween SARS-CoV-1 and SARS-CoV-2, including mation of the spike glycoprotein in the virus. genome length, receptor type, and the ability to As a result of this modification, the virus can stimulate cytokine storms8. attach to the Angiotensin-Converting Enzyme-2 The coronaviruses are ribonucleic acid (RNA) (ACE2) cell receptor, leading to accumulation viruses, which have a positive single-strand RNA. of clathrin beneath that area and penetration of This genus of viruses causes disease in humans the virus into the cell. ACE2 receptor has been and a wide range of animals9. The “Corona” term detected on the cell surface of several tissues, means crown in Latin, and the reason for their including stomach, liver, and lung12. The virus naming as coronaviruses is the observation of the can also trigger inflammatory responses called crown-like protein structures on these viruses Acute Respiratory Distress Syndrome (ARDS) under an electronic microscope. that can lead to a deadly severe condition and Coronaviruses are categorized into four sub- even death13. Two substantial protease enzymes, groups: alpha, beta, gamma, and delta. The first 3-chymotrypsin-like protease (3CLpro) and pa- two groups originate from mammals and can pain-like protease (PLPro) have essential roles cause zoonotic diseases in humans, while the in its viral replication process after it enters the last two groups emanate from birds and pigs. host cell via ACE2 receptors14. Expression of Figure 1. Schematic structure of COVID-19 and various proteins in its composition. 4164 Antiviral drugs proposed for COVID-19: action mechanism and pharmacological data several genes, such as AHCYL2, ZNF385B etc., Favipiravir appears to have a strong correlation with the ex- Favipiravir (under the brand name Avigan), pression of ACE2 and TMPRSS2 protein recep- also known as the T705 therapeutic compound, tors in human healthy and normal lung cells15. is a synthetic agent and antiviral product that was Various antiviral agents and adjuvant drugs first synthesized and marketed as an anti-influ- have been administered to treat COVID-19, and enza drug in Japan. The agent was discovered some of them could get emergency approval in in the biochemical section of the Toyoma labora- different countries. Other drugs, such as An- tory while studying the effects of several active giotensin-Converting-Enzyme inhibitors (ACEi), chemical compounds against the influenza virus. have also been used to treat COVID-19. However, The precursor of this drug is a substance called no clear correlation was reported between mor- A/PR/8/34, which was later named T1105. The tality rate and ACEi drugs in hypertension pa- anti-influenza effects of T1105 and its chemical tients with COVID-1916. Due to the possibility of derivatives were observed during their synthesis. secondary infection in these patients, antibiotics Favipiravir is also a derivative of the precursor have been applied as various protocols. The 10th T1105, formed by modifying and binding some day upon hospitalization is the most common day conjugates to the pyrazine moiety of T110518,19. for the onset and diagnosis of secondary infec- Favipiravir has desirable pharmacological charac- tions17. So far, no fully effective drug compound teristics. For instance, it has high bioavailability has been discovered against this virus. The anti- (~94%) and biocompatibility, efficiently binds to viral drugs, usually nucleoside analogues or in- about 54% of plasma proteins, and its maximum tracellular proteases, block the virus by prevent- concentration (Cm) peaks about two hours upon ing its entry into the cell or by interfering with utilization. Its Tmax and half-life increase after its replication inside the cell. In this study, we continuous administration of the drug. Drug ex- aimed to review famous antiviral drugs that have cretion is through renal elimination and is mainly already been used or could be effective against impacted by aldehyde oxidase and xanthine ox- SARS-CoV-2. The names of antiviral agents and idase. The hydroxylated form of Favipiravir is other terms that are described in this article are usually excreted renally. The cytochrome p450 summarized in Figure 2. complex enzyme does not metabolize Favipira- Figure 2. Schematic and straightforward overview of various terms discussed in this review article. 4165 F. Rommasi, M.J. Nasiri, M. Mirsaiedi vir, while CYP2C8, a member of this complex, is revealed it to be effective against other viruses, affected by Favipiravir. The half-life of this drug including the Nipah virus27, hepatitis C28, and is short and about 2.5 hours19,20.