Cellular protein identified as possible drug target to combat Lassa hemorrhagic fever

Lassa virus (LASV) is highly prevalent in Western Africa. The virus is typically transmitted to humans via contact with aerosols or the droppings and secretions of infected rodents. Infected individuals can develop Lassa fever (LF), a hemorrhagic fever disease associated with high morbidity and mortality. Notably, many LF survivors experience long-term side effects including sensory-neural hearing loss. Other than off-label use of ribavirin- which is of limited and controversial efficacy- there are no treatments for LF, nor any licensed vaccines.

The research, led by Juan Carlos de la Torre, PhD, of Scripps Research, in collaboration with the laboratory of Erica Ollmann Saphire, PhD, at La Jolla Institute for Immunology, was published in the Proceedings of the National Academy of Sciences (PNAS) on July 18, 2022.

To identify host cell proteins that contribute to LASV replication, the researchers implemented a new strategy that combined proximity proteomics with the use of a non-infectious cell-based LASV minigenome system that recreates the molecular processes involved in LASV replication. Proximity proteomics fuses a protein of interest to an enzyme that will label nearby proteins with a chemical tag, which facilitates their identification.

"Viruses don't operate in isolation," says Saphire. "They hijack and require molecules of the cell for their own purposes."

De la Torre compares the process to the way social networks can "leave traces of interactions" and provide information about how people might relate to one another, for example, whether two users are located in the same city or household, or if they are family members or acquaintances.

"Just as with social media users, some interactions between proteins make sense, and you can infer relationships between the two," he says. "Other protein interactions are casual or accidental and don't mean anything, but, for many others, further investigation is required to uncover their biological implications."

With this combined approach, they were able to identify 42 cellular proteins likely to play a role in the replication and spread of LASV. One of the identified host proteins-GSPT1-might be a potential drug target, as CC-90009, a drug that specifically targets and degrades GSPT1, exhibited antiviral activity against LASV without cytotoxicity. CC-90009 is currently in phase 1 clinical development for the treatment of acute myeloid leukemia, raising the possibility of its repurposing as an antiviral against LASV.

De la Torre notes that because this method of identifying viral-host cell protein interactions of interest can be done without the live, infectious LASV, this strategy does not require a biosafety level 4 (BSL4) lab, which are expensive to operate.

"We think the experimental approach we used could be a rubric for any other highly pathogenic virus," he says. "You would have to change the components, but conceptually, the same approach could potentially be applied with any highly pathogenic virus requiring BSL4."

Furthermore, says de la Torre, the identification of host cell proteins that are required for LASV replication can facilitate the repurposing of drugs currently being used for other indications as antivirals against LASV.

"This provides an advantage," he says, "since diseases like Ebola and Lassa are restricted to certain geographical areas, making it unlikely pharmaceutical companies will develop drugs specifically for them. Notably, Lassa and Ebola share a number of host cell proteins, which may facilitate the development of broad-spectrum antivirals by targeting host factors used by these two viruses."

He notes that a better treatment for LASV could also have an impact outside of Western Africa, as increased traveling to and from LASV endemic regions has resulted in the importation of LF cases into metropolitan areas outside Western Africa.

"People doing humanitarian aid in Western Africa, whether clinical work or social work, can get exposed, return to their home and then develop symptoms," he says. "What happens in many countries outside of Western Africa is that doctors who are not familiar with LF assume the disease is malaria and treat for that. When that doesn't work, by the time they realize what the disease is, it's usually too late."

Jingru Fang, Haydar Witwit, George Tsaprailis, and Gogce Crynen of Scripps Research are co-contributing authors of "Proximity interactome analysis of Lassa polymerase reveals eRF3a/GSPT1 as a druggable target for host-directed antivirals."

This research was supported by institutional 423 funds of La Jolla Institute of Immunology and NIH/NIAID grants AI125626 and AI128556.