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Abstract
Viral infections cause significant mortality every year. WHO has listed BetaCoronaviruses and Crimean-Congo Hemorrhagic Fever (CCHFV), a top priority for therapeutic research and development because of their high-level risk to national security and public health. Coronaviruses universally encode Papain-Like proteases (PLP) which assist in its replication process while also antagonizing the innate immune system. We investigated the closely related Alphacoronavirus genra PEDV to reveal whether PLPs across the coronavirus gena could be viewed as viable target to intervene in coronavirus immune evasion. Through biochemical and structural insights of the PEDV PLP, with the substrates Ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG-15), we found that it is like Betacoronaviruses in its deubiquitinase activity with a preference for K48 di-Ub. Additionally, the PEDV PLP does not readily process ISG-15 unlike its Betacoronavirus counterparts giving insight into how the PEDV PLP interacts with innate immunity. A similar emergent threat to public health is CCHFV, a BSL-4 virus with a 5-40% mortality rate. Recently the monoclonal antibody (mAb) 13G8 has been shown to target the CCHFV glycoprotein GP38 and can protect against lethality in a CCHFV mouse model. Here, we reveal the first time its GP38 epitope and how strain-strain differences among GP38s affect interactions with 13G8. Additionally, we discovered a higher affinity human derived mAb, CC5-17, that binds in a structurally divergent manner to that of 13G8 but overlaps its GP38 epitope. Coupled with sequence analysis, this new structural and in-vivo data blaze a new path to a broad-spectrum therapeutic use of these antibodies.