Macrodomains signify a novel goal for pathogens with pandemic potential

0

Scientists have long noted that the emergence and recurrence of infectious viral diseases, such as , pose an enormous health and economic threat to humankind. Both pharmaceutical and non-pharmaceutical preventive measures are needed to protect individuals from these viruses.

Study: The conserved macrodomain is a potential therapeutic target for coronaviruses and alphaviruses. Photo Credit: Design_Cells/Shutterstock

background

The current coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has highlighted the gap in preparedness to protect individuals from sudden viral outbreaks. This is largely due to the lack of development of antiviral agents against viruses that have the potential to cause pandemics.

Three coronaviruses, namely severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2, have caused notable epidemics and claimed millions of lives.

Another class of viruses, mosquito-borne alphaviruses, have the potential to cause a pandemic. Many individuals are affected by arthritis-causing alphaviruses such as CHIKV, Sindbis virus (SINV), and Mayaro virus (MAYV). These viruses cause chronic joint pain. Frequently, the viral RNA of both alphaviruses and coronaviruses persists, resulting in sustained immune stimulation and prolongation of symptoms.

Scientists have highlighted an urgent need for effective antiviral treatments for alphaviruses and coronaviruses. This would reduce hospitalizations, deaths and long-term disability from viral infections.

A new study

Previous studies have reported that both alphaviruses and coronaviruses contain a highly conserved macrodomain that could serve as a potential target for antiviral drug development. Furthermore, they reported that this newly identified macrodomain is essential for viral replication and virulence.

In a new study published in the journal Pathogens, researchers summarized the role of the macrodomain in viral replication and virulence and further explored the development of macrodomain inhibitors as antiviral agents.

A macrodomain is a conserved protein fold that exists as a single protein or is embedded within a larger protein. Previous studies have shown that the macrodomain structure includes a three-layered α/β/α fold and a conserved ADP-ribose binding pocket.

Previous studies have shown that mutations in the ADP-ribose binding regions of coronaviruses, alphaviruses, and HEV macrodomains cause inhibition of replication. In alphaviruses, the macrodomain mutation inhibits infection onset and viral RNA synthesis. Similarly, studies using mouse models have shown that mutations in the macrodomain domain of the SARS-CoV genome inhibit viral replication. These studies imply that macrodomain ADP-ribosylhydrolase activity is essential for both coronavirus and alphavirus pathogenesis. The primary function of the macrodomain is related to the virulence of viruses. The coronavirus macrodomain is also linked to the suppression of the interferon (IFN) response during infection. Researchers have reported that macrodomain mutant virus infection triggers IFN induction in the very early stages of infection. Therefore, macrodomain inhibitors could restore the robust host IFN response as well as viral replication.

Several ADP-ribosyltransferases (PARPs), which typically transfer an ADP-ribose moiety from NAD+ to target proteins, are activated by IFN and viral infection. PARPs are IFN-stimulated genes conserved in vertebrates as part of the innate response to infection.

(a) The structure of the SARS-CoV-2 macrodomain complexed with ADP-ribose (6WOJ);  (b) Hydrogen bonds (dashed lines) between amino acids in the binding pocket and ADP-ribose.  Obtained from Alhammad et al., 2020.

(a) The structure of the SARS-CoV-2 macrodomain complexed with ADP-ribose (6WOJ); (b) Hydrogen bonds (dashed lines) between amino acids in the binding pocket and ADP-ribose. Obtained from Alhammad et al., 2020.

Several studies have documented the importance of some PARPs in host antiviral responses. These studies have reported that overexpression of PARPs restricts the replication of several classes of RNA viruses. For example, PARP11 and PARP12 cause inhibition of Zika virus replication by ADP-ribosylating nonstructural proteins that target them for degradation.

Recent genomic analyzes of SARS-CoV-2 sequences, particularly all sequences of relevant variants, showed that critical residues for ADP-ribose binding remained highly conserved. This highly conserved sequence could be used as a potential target for the development of antiviral agents that could be effective across different virus families.

One of the advantages of choosing the macrodomain as a drug target is that over 500 structures are already available in the protein database. In addition, of these 500 sequences, 314 belong to viruses and 130 to humans. Structural analysis of the SARS-CoV-2 macrodomains has revealed the presence of three defined drug-ready “pockets” near the active site. These sites are considered potential targets for small molecule inhibitors. ADP-ribose binds to the largest pocket (P1), while the neighboring P2 and P3 could be further studied for structure-based drug discovery.

Several approaches such as B. computer-assisted docking, fragment-based screens, thermal shift assays and crystallographic screening, have independently determined several compounds, e.g. B. remdesivir, which bind to the SARS-CoV-2 macrodomain.

Conclusion

Previous studies have shown that the macrodomain is highly conserved in all coronaviruses, including seven human coronaviruses, and is critical for ADP-ribosyl hydrolase activity. The authors stated that the development of potent macrodomain inhibitors could play an essential role in preventing major virus outbreaks. They also found that the identification of selective inhibitors based on ADP-ribosyl hydrolase activity could be accomplished by screening larger libraries. This improves the chances of identifying effective macrodomain inhibitors. Furthermore, since coronaviruses and alphaviruses are veterinary pathogens, the discovery of macrodomain inhibitors could also play an important role in the treatment of infected animals.

Leave A Reply

Your email address will not be published.