Current Strategies of Antiviral Drug Discovery for COVID-19

Abstract

SARS-CoV-2 belongs to the family of enveloped, single-strand RNA viruses known as Betacoronavirus in Coronaviridae, first reported late 2019 in China. It has since been circulating world-wide, causing the COVID-19 epidemic with high infectivity and fatality rates. As of the beginning of April 2021, pandemic SARS-CoV-2 has infected more than 130 million people and led to more than 2.84 million deaths. Given the severity of the epidemic, scientists from academia and industry are rushing to identify antiviral strategies to combat the disease. There are several strategies in antiviral drugs for coronaviruses including empirical testing of known antiviral drugs, large-scale phenotypic screening of compound libraries and target-based drug discovery. To date, an increasing number of drugs have been shown to have anti-coronavirus activities in vitro and in vivo, but only remdesivir and several neutralizing antibodies have been approved by the US FDA for treating COVID-19. However, remdesivir’s clinical effects are controversial and new antiviral drugs are still urgently needed. We will discuss the current status of the drug discovery efforts against COVID-19 and potential future directions. With the ever-increasing movability of human population and globalization of world economy, emerging and reemerging viral infectious diseases seriously threaten public health. Particularly the past and ongoing outbreaks of coronaviruses cause respiratory, enteric, hepatic and neurological diseases in infected animals and human (Woo et al., 2009). The human coronavirus (HCoV) strains (HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1) usually cause common cold with mild, self-limiting upper respiratory tract infections. By contrast, the emergence of three deadly human betacoronaviruses, middle east respiratory syndrome coronavirus (MERS) (Zaki et al., 2012), severe acute respiratory syndrome coronavirus (SARS-CoV) (Lee et al., 2003), the SARS-CoV-2 (Jin et al., 2020a) highlight the need to identify new treatment strategies for viral infections. SARS-CoV-2 is the etiological agent of COVID-19 disease named by World Health Organization (WHO) (Zhu N. et al., 2020). This disease manifests as either an asymptomatic infection or a mild to severe pneumonia. This pandemic disease causes extent morbidity and mortality in the whole world, especially regions out of China. Similar to SARS and MERS, the SARS CoV-2 genome encodes four structural proteins, sixteen non-structural proteins (nsp) and accessory proteins. The structural proteins include spike (S), envelope (E), membrane (M), nucleoprotein (N). The spike glycoprotein directly recognizes and engages cellular receptors during viral entry. The four non-structural proteins including papain-like protease (PLpro), 3-chymotrypsin-like protease (3CLpro), helicase, and RNA-dependent RNA polymerase (RdRp) are key enzymes involved in viral transcription and replication. The spike and the four key enzymes were considered attractive targets to develop antiviral agents (Zumla et al., 2016). The catalytic sites of the four enzymes of SARS-CoV2 share high similarities with SARS CoV and MERS in genomic sequences (Morse et al., 2020). Besides, the structures of the key drug-binding pockets are highly conserved among the three coronaviruses (Morse et al., 2020). Therefore, it follows naturally that existing anti-SARS-CoV and anti-MERS drugs targeting these enzymes can be repurposed for SARS-CoV-2. Based on previous studies in SARS-CoV and MERS-CoV, it is anticipated a number of therapeutics can be used to control or prevent emerging infectious disease COVID-19 (Li and de Clercq, 2020; Wang et al., 2020c; Ita, 2021), these include small-molecule drugs, peptides, and monoclonal antibodies. Given the urgency of the SARS-CoV-2 outbreak, here we discuss the discovery and development of new therapeutics for SARS-CoV-2 infection based on the strategies from which the new drugs are derived.

Machine learning and network medicine approaches for drug repositioning for COVID-19

“…The development of computational approaches that can assist in the rational and fast discovery of treatments is critical for emergent infectious diseases such as COVID-19. [1][2][3]6,48 Drug repositioning, the re-use of drugs already on the market, can help to speed up the development of such treatments by prioritizing known safein-human drugs for clinical trials involving COVID-19 patients. In this paper, we proposed two machine learning approaches that can assist in the prioritization of drugs, together with a human-inthe-loop website tool, CoREx, to assist current research efforts for finding drugs with therapeutic efficacy against SARS-CoV-2.…”

“…A growing corpus of literature identifies several categories of treatment that revolves around the use of drugs with a mode of action that targets the molecular structure of the virus (virally targeted agents), or its cellular processes in the host (host-targeted agents), or those based on combinatorial therapies. [4][5][6][7] In this paper, we present two different machine learning approaches, and a webtool, for drug repurposing for COVID-19. Our first machine learning approach focuses on virally targeted agents and aims at ranking broad-spectrum antiviral (BSA) drugs.…”

Use of Monoclonal Antibody to Treat COVID-19 in Children and Adolescents: Risk of Abuse of Prescription and Exacerbation of Health Inequalities

“…Potent neutralizing mAbs often neutralize the receptor in S1, disabling receptor interactions [ 4 ]. The spike proteins of SARS-CoV-2 (SARS2-S) and SARS-CoV (SARS-S) are 77.5% identical by primary amino acid sequence, are structurally very similar and commonly bind the human angiotensin-converting enzyme 2 (ACE2) protein through their S1B domain [ 5 , 6 ]. Receptor interaction is known to cause irreversible conformational modifications in coronavirus spike proteins enabling membrane fusion [ 7 ].…”

Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19

“…Accordingly, the discovery of curative treatments is essential to fight COVID-19. Therefore, many strategies are being followed to discover more and better treatments for COVID-19, for example, the development of inhibitors of the key enzymes of SARS-CoV-2 like RNA-dependent RNA polymerase (favipiravir and remdesivir), papain-like protease (disulfiram), helicase (ivermectin), and 3-chymotrypsin-like protease (lopinavir and ritonavir) [ 11 ]. The therapeutic strategies to combat COVID-19 also revolve around the drug repurposing approach, i.e., identification of effective treatment from the pool of existing drugs [ 12 ].…”