Active Genetics & Molecular Biology Cells, Biochemistry & Physiology

Coronaviruses: linking polyprotein processing and replication complex function

Funder Wellcome Charity-funded
Recipient organisation University of Liverpool
Funding £2.5M
Period Dec 2023 — Mar 2032

In plain English

AI plain-English summary

Coronaviruses chop their own long protein chains into specific fragments to control whether they copy their genetic material early or late in infection, but no one knows exactly which fragments do what. This matters because the two main proteases that perform the chopping are already targets of existing drugs like Paxlovid, yet the precise roles of the dozens of resulting protein pieces—especially the partially-cut "precursors"—remain a black box. Without knowing which fragments direct early versus late replication, researchers cannot rationally design the next generation of antiviral compounds. If this project succeeds, it will map the timing, location, and function of these precursors across three coronavirus families. That mechanistic map could reveal new drug targets hidden in the replication cycle itself, not just in the proteases. The work is fundamental science: it asks how a virus’s own molecular machinery switches modes. Similar fundamental studies of viral replication enzymes have previously underpinned the development of treatments for HIV and hepatitis C. A clearer picture of coronavirus polyprotein processing could lay the same kind of groundwork for future pandemic preparedness.

View original technical description
Coronaviruses are the causative agents of recent human pandemics and common human and animal diseases. Despite their importance, significant details of the coronavirus life cycle remain unknown. Coronaviruses produce the proteins required for genome replication by translating two long polyproteins: pp1a and pp1ab. Two viral proteases process both polyproteins into the components of the viral replication complex. This proteolytic cleavage results in over 100 theoretical fully and partially-cleaved products. The latter are termed ‘precursors’ and play vital roles in the replication of similar RNA virus families. For the coronaviruses, it has been speculated that early in infection, long partially-cleaved precursors direct antisense RNA synthesis. Late in infection, fully-cleaved polyprotein products direct sense RNA synthesis. However, experimental data and a mechanistic understanding of specific polyprotein cleavage products' roles is lacking. Understanding this process may pave the way for the next generation of antiviral drugs. In this proposal, we will: - Determine: the dynamics and subcellular localization of stable polyprotein precursors across the alpha- beta- and gammacoronaviridae. - Uncover: mechanisms of cellular and viral control of polyprotein dynamics using genetic and inhibitor-based approaches. - Define: the mechanistic function of polyprotein precursors in coronavirus RNA replication.

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Researchers

Edward Emmott (EPMC Awardee)

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Original classification

Career Development Award

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