COVID-19 drug candidate with wide-ranging antiviral activity

Scientists have revealed that seven coronaviruses can infect human beings. Some human coronaviruses (HCoV) that cause the common cold are HCoV-229E, -NL63, -OC43, and -HKU1. Other members that have caused epidemics with a high rate of mortality are severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV). At present, the ongoing coronavirus disease 2019 (COVID-19) pandemic has been caused by another member of the coronavirus family, namely, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Brilacidin, a COVID-19 Drug Candidate, demonstrates broad-spectrum antiviral activity against human coronaviruses OC43, 229E and NL63 through targeting both the virus and the host cell. Image Credit: sdecoret/ Shutterstock

Background

Among the coronaviruses, MERS-CoV, SARS-CoV- and SARS-CoV-2 are the three highly pathogenic human coronaviruses. At present, SARS-CoV-2 has infected around 250 million individuals and claimed more than five million lives worldwide. Several COVID-19 vaccines have received emergency use authorization (EUA) from the global regulatory bodies. Subsequently, vaccination has commenced in many countries across the world. Among the available COVID-19 vaccines, two mRNA-based vaccines, BNT162b2 and mRNA-1273, have been developed by Pfizer- BioNTech and Moderna, respectively. Another vaccine to receive EUA is Johnson & Johnson’s JNJ-78436735.

Although clinical trials have shown that all the available vaccines are effective against the SARS-CoV-2 virus, the emergence of the variants owing to mutation has threatened the efficacy of the vaccines. Owing to this reason, small molecular antiviral drugs are important complements to vaccines to help contain pandemics.

Previous studies have shown that host defense peptides (HDPs), also known as antimicrobial peptides (AMPs), are typically small peptides of approximately 12 to 50 amino acids. These are the first line of defense against foreign pathogens. These proteins are expressed in the neutrophils and mucosa. Scientists have extensively studied HDPs to determine effective antibiotics, antivirals, antifungals, and anticancer agents.

The majority of HDPs possess an amphiphilic structure with a positively charged face and a hydrophobic face. Regarding their mode of action, scientists revealed that HDPs damage the bacterial cell membranes by interacting with the negatively charged phospholipid headgroups.

The study

Brilacidin is a small synthetic HDP that possesses antibacterial activity against both Grampositive and Gram-negative bacteria. At present, it is in Phase 2 clinical trials. Previous studies have demonstrated the antibacterial mode of action of Brilacidin, which includes both membrane disruption and immunomodulation. Interestingly, this compound is presently undergoing a clinical trial as a SARS-CoV-2 antiviral drug candidate for hospitalized COVID-19 patients.

A recent study reported that Brilacidin displayed a potent inhibitory effect against the SARS-CoV-2 virus. Researchers reported its mechanism of action to be disruption of viral integrity, which can block the entry of the virus into the host cell. However, no evidence related to the effect of Brilacidin on host cells and the antiviral property of Brilacidin against other HCoVs is documented.

A new study, published on the bioRxiv* preprint server, investigated the antiviral activity and mechanism of action of Brilacidin against multiple human coronaviruses. This study also demonstrated that Brilacidin inhibits SARS-CoV-2 pseudovirus entry into multiple cell lines. This compound possesses dual antiviral mechanisms of action, which involves targeting both the virus and the host cell.

Researchers revealed that acetyl Brilacidin could not inhibit SARS-CoV-2 pseudovirus entry. Interestingly, the current study reported the influence of heparin, a heparan sulfate proteoglycans (HSPGs) mimetic, in reducing the inhibitory activity of Brilacidin. This result highlights a new mechanism of action of Brilacidin that involves its binding to HSPGs on the host cell, thereby blocking viral attachment. The current study reported HSPGs as an attachment factor for SARS-CoV-2.

The authors revealed that Brilacidin has broad-spectrum antiviral activity against many HCoVs such as HCoV-229E, HCoV-OC43, and HCoV-NL63. Interestingly, they found that the antiviral mechanism against these viruses is analogous to its virucidal effects and binding to HSPGs. Scientists further reported that, in the presence of heparin in cell culture, Brilacidin partly loses its antiviral capability against many HCoVs, e.g., HCoV-229E, HCoV-OC43, HCoV-NL63. According to the drug time-of-addition experiment, Brilacidin functions as an antiviral agent at two individual steps, i.e., when the virus is initially attached to the host cell and early entry after invading into the host cells.

Another important aspect of this study is the drug combination therapy, which revealed that Brilacidin has a strong synergistic effect with remdesivir (FDA-approved SARS-CoV-2 therapeutics) against HCoV-OC43 in cell culture.

Conclusion

The current research showed that Brilacidin is a potential antiviral agent with a dual antiviral mechanism of action, i.e., targeting host cell surface HSPGs to inhibit viral attachment and disrupting the integrity of viral particles, making them inactive. The dual action could slow down the development of viral resistance. Considering its mechanism of action and broad-spectrum antiviral activity against several coronaviruses, the authors recommend the development of Brilacidin based treatment that could be effective against the existing and future emerging coronaviruses.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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.