Coronavirus Antivirals Updated

Coronaviruses are spherical viruses with a large genome (approximately 27 to 32 kb) enclosed in a lipid bilayer with surface glycoprotein projections that give the virus the appearance of having a crown, hence the name coronavirus. There are four types of coronavirus: Alphacoronaviruses and Betacoronaviruses infect only mammals, while Gammacoronavirus and Deltacoronavirus infect birds. In humans coronaviruses cause respiratory tract infections with symptoms ranging from mild, similar to the common cold, to severe pneumonia-like symptoms, as seen with SARS (severe acute respiratory syndrome), MERS (Middle East respiratory syndrome) and COVID-19. They are also responsible for a number of economically important animal diseases, including avian infectious bronchitis virus (IBV) and porcine transmissible gastroenteritis virus (TGEV).

Figure 1: Immunofluorescence assay using Rabbit Anti-SARS-CoV Nucleocapsid (N) Antibody (#NBP2-44205 - part of SARS Nucleocapsid Protein Antibody Pack #NBP3-05695), showing viral protein synthesis. VeroE6 cells were infected with rSARS-CoV-2. Mock: non-infected cells. At 48 hpi cells were fixed and prepared for immunofluorescence staining with primary antibodies directed against double-stranded RNA (dsRNA) [green] and SARS-CoV Nucleocapsid (N) [red]. Nuclear Counterstain (DAPI, Cat. No. 5748) [blue].

SARS-CoV-2 Antivirals

SARS-CoV-2 is a coronavirus responsible for the outbreak of COVID-19, a form of severe acute respiratory syndrome (SARS) that emerged in the city of Wuhan, China, in 2019. SARS-CoV-2 enters the lower respiratory system causing viral pneumonia; it may also affect the gastrointestinal system, heart, kidney, liver, and central nervous system leading to multiple organ failure.

Several SARS-CoV-2 viral proteins are being investigated as potential therapeutic targets. The spike (S) protein, a structural protein on the outside of the nucleocapsid of coronaviruses, is one such protein, which has potential as a target for coronavirus antiviral medicines. The virus is able to enter the host cell by binding of the S protein to the host protease angiotensin converting enzyme 2 (ACE2) on the cell surface. The host protein ACE2, which acts as a receptor for SARS-CoV-2, is also a possible target for antiviral therapies. ACE2 is highly expressed in lung alveolar cells and high expression levels are also seen in glandular cells, endothelial cells, and enterocytes in the gastrointestinal system. Another host protein, the protease TMPRSS2 is also essential for host cell invasion, by activating the S protein and enhancing cell entry by SARS-CoV-2. The SARS-CoV-2 S-protein is also thought to be cleaved by the endoprotease furin.

Two viral proteases, SARS coronavirus main proteinase (Mpro also known as 3C-like protease or 3CLpro) and papain-like protease, (PLpro) both of which are essential for virus replication, are also being investigated as potential antiviral targets. These proteases cleave the two translated polyproteins, PP1A and PP1AB, into functional proteins. SARS-CoV and SARS-CoV-2 3CLpro gene sequences have approximately 96% homology.

MERS

MERS is another severe respiratory infection caused by MERS-CoV that emerged in the Middle East region in 2012. MERS-CoV was originally thought to have been transmitted from camels, although more recently it has been suggested that it originated in bats. Unlike SARS-CoV-2, MERS-CoV uses dipeptidyl peptidase 4 (DPP4) as a receptor to infect lung cells, which could be a target for antivirals to treat this infection.

Compound Repurposing

Repurposing existing therapies is an approach being widely investigated to discover treatments for COVID-19. Screening compound libraries, such as the Tocriscreen library of FDA approved drugs (Cat. No. 7200), for their activity against known viral or host targets could aid the rapid discovery of products that can prevent/treat the infection or alleviate symptoms in patients.