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1.
Topics in Antiviral Medicine ; 30(1 SUPPL):63, 2022.
Article in English | EMBASE | ID: covidwho-1881050

ABSTRACT

Background: During the beginning of the SARS-CoV-2 pandemic the D614G mutation in Spike protein appeared and became the first dominant variant across the globe. This mutation led to increased infectivity and stability of the spike protein and its importance is highlighted by being the one common mutation between every spike variant of concern that has come after the original. We asked how dependent spikes of subsequent lineages were on the D614G mutation and whether lineages in the absence of D614G had other mutations that increased fitness compared to the ancestral Wu-1 strain. Methods: We explore the contribution of D614G and other identified stabilizing mutations on spike mediated infectivity by incorporating them into different spike constructs. Psuedotyped lentiviral and SARS-CoV-2 virus like particle (VLP) reporters are utilized along with biochemical analysis probing expression, processing, and incorporation of spike constructs into VLPs. Results: We identify that the D614G mutation is critical for stability, infectivity, and virion loading in a number of prominent variants of concern and dominant lineages. Studying spike variants that were in circulation in absence of D614G mutation led to identification of a number of mutations at the S1 S2 interface performing similar stabilizing spike function as D614G, increasing infectivity compared to the ancestral Wu-1 Spike. The dependence on the presence of D614G or other stabilizing mutations only increased in the presence accumulating S1 mutations and specifically mutations that increase processing of spike by host furin protease, such as P681R. Conclusion: Though D614G increased stability and infectivity on the Wu-1 background, other mutations are able to perform the same role. However as more mutations accumulated in spike in the presence of D614G other stabilizing mutations are unable to fully rescue infectivity in absence of D614G, indicating a clear reliance on D614G for function. Identifying this as a critical mutation in the spike may inform future vaccine design and prediction of possible mutations that are compatible with and functional on D614G containing spike lineages.

2.
Virus Research ; 292:11, 2021.
Article in English | Web of Science | ID: covidwho-1043007

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.

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