The recent outbreaks of human coronaviruses: A medicinal chemistry perspective

Abstract

Coronaviruses (CoVs) infect both humans and animals. In humans, CoVs can cause respiratory, kidney, heart, brain, and intestinal infections that can range from mild to lethal. Since the start of the 21st century, three β‐coronaviruses have crossed the species barrier to infect humans: severe‐acute respiratory syndrome (SARS)‐CoV‐1, Middle East respiratory syndrome (MERS)‐CoV, and SARS‐CoV‐2 (2019‐nCoV). These viruses are dangerous and can easily be transmitted from human to human. Therefore, the development of anticoronaviral therapies is urgently needed. However, to date, no approved vaccines or drugs against CoV infections are available. In this review, we focus on the medicinal chemistry efforts toward the development of antiviral agents against SARS‐CoV‐1, MERS‐CoV, SARS‐CoV‐2, targeting biochemical events important for viral replication and its life cycle. These targets include the spike glycoprotein and its host‐receptors for viral entry, proteases that are essential for cleaving polyproteins to produce functional proteins, and RNA‐dependent RNA polymerase for viral RNA replication.

Kinases as Potential Therapeutic Targets for Anti-coronaviral Therapy

“… 87 In murine models of dengue and ebolaviruses, the drug combination sunitinib/erlotinib has been shown to minimize morbidity and mortality. 7 However, the dosage required for inhibiting AAK1 and GAK by sunitinib and erlotinib would be much higher in COVID-19 patients. 86 …”

“…AXL facilitated virus entry and modulated the antiviral state of human Sertoli cells during Zika virus infection. 7 AXL inhibition led to decreased suppressor of the cytokine signaling-1 (SOCS1) and SOCS3 proteins, increased expression of IFNγ, and reduced replication. In a recently published study, the authors discovered that AXL interacts with the SARS-CoV-2 S glycoprotein on the host cell membrane, allowing the virus to enter the cell.…”

“…It is essential to comprehend the coronavirus’s basic features and life cycle to develop potential antiviral therapeutics. Coronaviruses are enveloped, positive-sense RNA viruses with the world’s largest viral RNA genome (∼26–32 kilobases) 7 that comprises about 30 000 nucleotides. So far, seven human coronaviruses have been discovered, and they are classified into four main genera (α, β, γ, and δ) under the family Coronaviridae : 8 α-CoVs are (i) HCoV-229E and (ii) HCoV-OC43, and β-CoVs are (iii) HCoV-HKU1, (iv) HCoV-NL63, (v) SARS-CoV-1, (vi) MERS-CoV, and (vii) SARS-CoV-2 ( Figure 1 ).…”

3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents

“… 20 The indispensable role of 3CL pro in the viral life cycle and the absence of closely related human homologues establish 3CL pro as an ideal target for the development of antiviral agents for coronavirus diseases. 7 , 15 , 21 A large part of the drug discovery program for the control of SARS in 2003 and MERS in 2012 has therefore been dedicated to the development of potent 3CL pro inhibitors. 7 , 15 , 21 3CL pro of SARS-CoV-2 shows 99% homology and 96% identity to that of SARS-CoV-1.…”

“… 7 , 15 , 21 A large part of the drug discovery program for the control of SARS in 2003 and MERS in 2012 has therefore been dedicated to the development of potent 3CL pro inhibitors. 7 , 15 , 21 3CL pro of SARS-CoV-2 shows 99% homology and 96% identity to that of SARS-CoV-1. 10 …”