TSRI unlocks secrets of deadly virus and finds clues to cancer treatment in bacteria
LA JOLLA, Calif. & JUPITER, Fla.—A focus on microscopic work at The Scripps Research University (TSRI) has yielded some big answers in both virology and oncology studies of late. Most recently, a team at TSRI has pinpointed key differences between Ebola and Marburg virus and how an antibody known as MR191 works to neutralize Marburg. Their work appeared in a study titled “The Marburg virus-neutralizing human monoclonal antibody MR191 targets a conserved site to block virus receptor binding,” which was published in Cell Host & Microbe.
Marburg virus is a hemorrhagic virus that, like Ebola, is a member of the Filoviridae virus family. The virus has a mortality rate of up to 88 percent, and there are no proven treatments for Marburg beyond supportive care. An outbreak in Angola in 2005 resulted in 329 deaths among 374 infected individuals. The World Health Organization (WHO) reported an outbreak in eastern Uganda in October 2017. Before WHO reported on Dec. 8 that the outbreak had been controlled, three cases (reported as one probable and two confirmed) were reported by Nov. 4, all of whom died.
In the recent study, the TSRI team generated a map of the Marburg virus’ structure, using X-ray crystallography to show how MR191 targets and neutralizes the virus. The compound works by mimicking the host receptor and slotting itself into a spot on the surface of the virus known as the receptor binding site. With that site plugged, the virus can’t attach to human cells and spread infection. The imaging also showed them that Marburg virus has a “wing” that sticks out of its surface, one of only two known sites where protective human antibodies can bind to the virus.
“MR191 is a human IgG1 antibody. It was isolated from a human survivor of Marburg virus by James Crowe Jr.’s lab (an author on the paper) and originally published in 2015. Since that time it has been undergoing R&D to improve its expression and efficacy,” TSRI graduate student Liam King, first author of the study, tells DDNews. Crowe is a member of the Departments of Pediatrics, Pathology, Microbiology and Immunology at Vanderbilt University Medical Center, as well as the Vanderbilt Vaccine Center.
Their research also showed them that for all that Ebola and Marburg hail from the same genetic family, they have some key differences. While the Ebola virus also has a “wing,” the wing on the Marburg virus folds around the outside of its glycoprotein spike. In addition, though both viruses use a glycan cap to shield their receptor binding sites from the immune system, MR191 can bypass that cap on Marburg virus, which antibodies against Ebola are not capable of doing.
“That finding and others in this structure tell us that Marburg is constructed differently from its cousin, the Ebola virus,” Dr. Erica Ollmann Saphire, a TSRI professor and senior author of the study, said in a press release. “That means the therapeutic strategy for one may need to be different from the other.”
She went on to note that the next goal in this research is to explore how mutations in Marburg virus evade antibodies, and apply that information in search of second-line treatments. Study collaborators from Vanderbilt University have licensed MR191 to Mapp Biopharmaceutical Inc. as its commercial partner.
At the Florida campus of TSRI, researchers who previously identified LNM E1, a prostate cancer-killing compound, have further advanced the leinamycin (LNM) molecules thanks to targeted research into genetic information stored in the genomes of bacteria. Their work appeared in the Proceedings of the National Academy of Sciences USA.
The LNM family of compounds are natural products produced by a bacterium that resides in soil. Thus far, lead investigator Dr. Ben Shen—a TSRI professor and co-chair of the Department of Chemistry—and collaborators only knew of LNM within the LNM family. When they edited the bacterium’s genome, they produced LNM E1, and showed in research back in 2015 that LNM E1 could react with reactive oxygen species in prostate cancer cells to trigger death.
In order to find analogues of LNM E1, the team leveraged the Natural Products Library Initiative on the TSRI Florida campus. This library consists of purified natural products, partially pure fractions, crude extracts and bacterial strains collected worldwide that can be used for drug discovery screening.
As the authors note in their paper, “By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF–SH didomains. Further analysis of the representative genomes from each of the clades identified 28 LNM-type gene clusters.”
Analyzing their results and isolating several of the new LNM compounds yielded new answers about the structure of LNM compounds, such as that while bacteria have evolved to produce LNMs with many similar characteristics, small differences can impact how effect the natural products are against cancer cells. In advancing this research, the team will be studying LNM molecule interactions with cancer cells to see how such changes affect their response.
“These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature’s rich biosynthetic repertoire,” the authors remarked. “Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect nature’s biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity.”
“The technological advances we’ve made enable us to quickly identify sources of these types of natural products,” added Shen. “This could dramatically impact the drug lead pipeline.”