SARS-CoV-2's amyloid-driving nucleoprotein could inform future therapeutic research

Amyloids are commonly associated with misfolded proteins that increase the risk of developing Alzheimer’s disease. However, new research led by researchers at the University of California Los Angeles and the University of Texas Southwestern Medical Center in the US suggests that functional amyloid fibrils could play an integral role in developing coronavirus disease 2019 (COVID-19) treatments.

Amyloid fibrils could help create a greater understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein (NCAP) and subsequent viral replication. In this study, NCAP created amyloid fibrils when undergoing liquid-liquid phase separation. As a result, the team successfully created several peptide inhibitors designed to disrupt NCAP fibril formation.

The research team writes:

By aiming our inhibitors against conserved as well as non-conserved regions in the NCAP, it may be possible to provide both global and strain specific coronavirus therapeutics.”

The study “Inhibition of amyloid formation of the Nucleoprotein of SARS-CoV-2” is available as a preprint on the bioRxiv* server, while the article undergoes peer review.

Results

NCAP appears to be related to other fibril-forming proteins. The team found RNA could stimulate fibril formation of NCAP and liquid-liquid phase separation. In addition, RNA-induced liquid-liquid phase separation droplets contained amyloid fibrils. The researchers suggest that amyloid fibrils are evidence of a correlation between processes for amyloid fibrils and liquid-liquid phase separation.

These similarities suggest that NCAP fibrils function in its action of encapsulating RNA in viral replication. The hairpin-possessing viral RNA, Site2hp, exhibits strong binding to NCAP and some binding to its DD-Cterm segment, but weak to no binding to Nterm-RBD and to the low-complexity domain itself,” explained the team.

Based on the findings, several proteins are involved in binding RNA to NCAP, showing further similarities. The researchers also suggest NCAP’s fibril forming function is directly involved with its ability to produce liquid-liquid phase separation.

Evidence also suggests NCAP’s fibril formation is involved in increasing viral infectivity. The results showed a change from a liquid-like to a gel-like state upon prolonged incubation with the Site2hp RNA.

The next step researchers took was targeting and disabling the NCAP’s fibril formation function. The rationale was that disrupting NCAP fibrils could decrease SARS-CoV-2 ability to cause infection.

They created their own peptide inhibitors by targeting six fibril-driving segments based on template sequences of homo-steric zippers. A total of 60 peptide inhibitors were tested against the fibril formation of NCAP.

Inhibitors based on the AALALL fibril-driving segment were the most effective in weakening low-complexity domain fibril formation. However, this result was dose-dependent. The results suggest AALALL’s strong stabilizing interactions make it the best candidate for future therapeutics.

However, the researchers point out that the candidates chosen for their inhibition of fibral formation of the low-complexity domain may not be as strong in weakening fibril formation of full NCAP. There were a few reported peptide inhibitors that enhanced NCAP’s fibril formation process.

The researchers infer that other NCAP areas beyond the low-complexity domain may be used for creating NCAP fibrillation.

This implies that additional segments of NCAP, such as the shorter low-complexity sequence near the C-terminus, are capable of driving NCAP fibrillation. It is possible, however, that candidates lacking in vitro inhibition of fibril formation of the full NCAP may nevertheless affect viral function,” wrote the team. “It will be necessary to evaluate all inhibitor candidates for their ability to reduce viral replication in SARS-CoV-2 infected cells.”

In addition, therapeutics targeting the interactive interface in the amyloid spine could pressure the virus to mutate and potentially disrupt protein function.

In summary, the SARS-CoV-2 NCAP protein undergoes liquid-liquid phase separation accompanied by formation of amyloid-like fibrils driven at least in part by the self-association of its low-complexity domain and interaction with RNA. Based on three atomic structures of the fibril-driving segments of NCAP, we designed peptides that affect NCAP fibril formation. These peptides may offer a new approach to anti-COVID therapies.”

Given amyloid’s role in movement disorders and dementia such as Alzheimer’s disease, future therapeutics will also need to manage amyloid fibrils.

*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.

Journal reference:
Jocelyn Solis-Moreira

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.

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