Three RNA virus families have been responsible for epidemics and pandemics throughout recorded human history. Scientists at Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, have broken down the biology, genomic makeup, life histories, and key drug targets of these three viral families. The authors also identified structurally diverse natural compounds in the marine ecology that could be used to develop antiviral therapeutics with the potential to disrupt the spread of these notorious viruses and highlight possible treatment strategies.
Natural products have been an inspiration for the development of new pharmaceuticals with nearly half of all present small-molecule drugs designed or derived based on some natural compound. “As we search for new answers to the threat of global pandemics, where better to begin looking than in nature?” noted the authors in the article, which is titled, “Natural Products with Potential to Treat RNA Virus Pathogens Including SARS-CoV‑2,” published in the Journal of Natural Products.
The research team from Scripps Oceanography’s Center for Marine Biotechnology and Biomedicine (CMBB) is developing a library of compounds with medicinal potential—antivirals, antibacterials, antiparasitics, anticarcinogenics—from natural products found in the marine environment. “Different natural product researchers focus on different classes of organisms; some look at terrestrial plants as a focus, some at soil bacteria, others at marine life forms. The search of marine life for bioactive natural products is a more recent pursuit, and as a result we are still in the phase of learning what types of molecules are out there,” said William Gerwick, PhD, professor of oceanography and pharmaceutical sciences and director, NIH Training Grant on Marine Biotechnology.
There are some 21 current pharmaceuticals that trace their discovery to a marine natural product, and more are appearing each year. A drug known as Marizomib entered the final stages of clinical trials as a potential treatment for brain cancers earlier in 2020. The drug came from a genus of marine bacteria that CMBB researchers had originally collected in seafloor sediments in 1990.
Within these families—Coronaviridae, Flaviviridae, and Filoviridae—are viruses that have led to COVID-19, dengue fever, West Nile encephalitis, Zika, Ebola, and Marburg disease outbreaks. These viruses use RNA instead of DNA to store their genetic information, a trait that helps them to evolve quickly.
“We wanted to evaluate the viruses that are responsible for these deadly outbreaks and identify their weaknesses,” said Mitchell P. Christy, PhD candidate and first author of the study. “We consider their similarities and reveal potential strategies to target their replication and spread. We find that natural products are a valuable source of inhibitors that can be used as a basis for new drug development campaigns targeting these viruses.”
“There are several common targets for antivirals among the RNA viruses Coronaviridae, Flaviviridae, and Filoviridae. The most common is the enzyme responsible for synthesis of RNA, the RNA-dependent RNA polymerase. Also, proteases are involved in these viral life cycles. The host cell proteases, cathepsin L and TMPRSS2, have roles in the viral uptake into cells for many of the viruses in these three groups,” said Gerwick.
Effective antiviral drugs are also critically needed for managing COVID-19 infection in unvaccinated individuals or in cases where the efficacy of a vaccine decreases over time, the researchers noted. “It is simply common sense that we should put into place the infrastructure necessary to more rapidly develop treatments when future pandemics occur,” the authors concluded. One such recommendation is to create and maintain international compound libraries with substances that possess antiviral, antibacterial, or antiparasitic activity.
“We hope to inspire our diverse colleagues to further explore natural products as potential treatments for these viral diseases by sharing some of these leads from nature. We are pursuing a lead molecule we discovered called gallinamide A, which shows potent anti-COVID-19 activity through its inhibition of cathepsin,” said Gerwick.