A study on SARS-CoV-2 proteins for the development of COVID-19 drugs

Several viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome-CoV (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belong to the coronaviridae family of enveloped, positive-strand RNA viruses which infect amphibians, birds, and mammals.

The causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic is SARS-CoV-2. Despite many similarities, there are differences in the genomic sequence, function, and structure between these coronaviruses.

Understanding the mode of infection and identifying the sites of virus-host interaction of these three coronaviruses is extremely important for the development of potential therapies. Hence, a detailed study of individual virus proteins is crucial.

Previous studies have revealed the significance of individual virus proteins to pathogenicity and many other functions. Some of the functions include initiation of the virus replication cycle and promotion of virus gene expression within the host, seizing host proteasome function, evasion of the host immune response, etc.

Considering the significance of individual proteins, a new review has been published in the journal Molecular and Cell Biology, which included research available through Pubmed before mid-February 2021.

In the SARS-CoV-2 genome, open reading frame (Orf)1ab, is the largest gene located at the 5’ end and encodes polyproteins PP1ab and PP1a. These polyproteins are cleaved into 16 non-structural proteins, i.e., Nsp1-16, while genes at the 3’ end sequence encode four structural proteins, namely, spike (S), envelope (E), membrane (M), and nucleocapsid (N), and eight additional accessory proteins.

The authors of the review have grouped the virus proteins into three categories, (a) host-entry, (b) self-acting, and (c) host-interacting. Additionally, individual SARS-CoV-2 proteins are evaluated to be either directly targeted by drugs or block virus-host interactions.

Host-entry

Several studies are available that focus on the interaction between the host membrane and the SARS-CoV-2 spike. This interaction is correlated with transmission and infectivity.

In a nutshell, the spike protein of the virus interacts with the host plasma membrane, after which proteases enzyme enables the fusion of the membrane. Subsequently, the virus achieves host cell entry. Both SARS-CoV and SARS-CoV-2 use host angiotensin-converting enzyme 2 (ACE2) receptor, but MERS-CoV spike protein interacts with host dipeptidyl peptidase (CD26) receptor to gain entry.

The authors suggest that NRP1 is an important cofactor, and could initiate the virus entry into the host cell with low ACE2 expression (e.g., olfactory epithelium). This cofactor enhances SARS-CoV-2’s ability to infect different cell types and tissues.

Minireview: Understanding individual SARS-CoV-2 proteins for targeted drug development against COVID-19. Image Credit: Design_Cells / Shutterstock

Self-acting

As viruses depend on the cellular mechanism of the host for translation and replication, several viral proteins get modified to interact with host proteins.

These modified proteins target the host cell molecular pathways and make it favorable for it to thrive. Some of the replication-based virus proteins are papain-like cysteine protease (PLpro) that are encoded within Nsp3 and 3-chymotrypsin-like protease (3CLpro) encoded by Nsp5. Nsp13 possesses NTPase and RNA helicase activities, which involve viral RNA processing, i.e., replication, transcription, translation, and encapsidation.

RNA-dependent RNA polymerase (RdRp) complex is another vital virus-encoded factor for replication. Proofreading during RNA replication is carious out by Nsp14.

Host-interacting

Viruses mainly depend on host cell machinery for their survival. Only a few structural proteins like spike protein interact with ACE2/TMPRSS2/Furin to gain host cell entry. The majority of virus-host interactions occur intracellularly, and these interactions focus on taking over host cell systems.

The virus proteins whose primary function is associated with virus replication are generally highly conserved. However, proteins whose function is host immune evasion are not conserved as they need to constantly adapt to counteract new host protection tactics.

Additionally, blocking virus-specific proteins is favorable as it is less likely to generate side effects since the host systems would not carry homologous proteins.

The majority of research has indicated that PLpro (Nsp3) inhibitors can block SARS-CoV-2 PLpro activity. VIR250 and VIR251 are reported as two novel compounds that can specifically inhibit protease activity of SARS-CoV and SARS-CoV-2, but not MERS-CoV.

In vitro studies have revealed that GRL-0496 and GC376 can effectively inhibit SARS-CoV 3CLpro. Remdesivir, a broad-spectrum antiviral, was the only approved drug for the treatment of COVID-19, but more recently, researchers have found little or no effect on disease progression.

A study has estimated around 40% of SARS-CoV-2-interacting proteins were linked with host endomembrane compartments or vesicle trafficking pathways.

By comparing the interaction networks with pharmacological profiles using pharmacological agent library, around 69 compounds were identified which target 62 virus-host protein interactions.

In vitro studies of these drugs have shown inhibition of virus-targeted interaction with translation pathways and sigma-1 and sigma-2 receptors to be most promising.

One of the promising candidates, undergoing clinical trial, is indomethacin, an anti-inflammatory agent which targets Nsp7-PGES-2.

Other potential candidates are chlorpromazine, amiodarone, tamoxifen, and propanolol, all of which target Nsp6-SIGMAR1. Currently, the tyrosine kinase inhibitor is undergoing clinical trials for the treatment of COVID-19.

The authors of this study believe that understanding individual virus proteins and their interaction with the host could help identify more effective drugs to enhance the patient immune system.

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.