A novel highly potent inhibitor of TMPRSS2-like proteases blocks SARS-CoV-2 variants of concern and is broadly protective against infection and mortality in mice

Abstract

SummaryThe COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced against emerging variants of concern (VOCs) 1,2. Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against VOCs 3,4. Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases (TTSPs), such as TMPRSS2, whose essential role in the virus lifecycle is responsible for the cleavage and priming of the viral spike protein 5–7. Here, we identify and characterize a small-molecule compound, N-0385, as the most potent inhibitor of TMPRSS2 reported to date. N-0385 exhibited low nanomolar potency and a selectivity index of >106 at inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids 8. Importantly, N-0385 acted as a broad-spectrum coronavirus inhibitor of two SARS-CoV-2 VOCs, B.1.1.7 and B.1.351. Strikingly, single daily intranasal administration of N-0385 early in infection significantly improved weight loss and clinical outcomes, and yielded 100% survival in the severe K18-human ACE2 transgenic mouse model of SARS-CoV-2 disease. This demonstrates that TTSP-mediated proteolytic maturation of spike is critical for SARS-CoV-2 infection in vivo and suggests that N-0385 provides a novel effective early treatment option against COVID-19 and emerging SARS-CoV-2 VOCs.

Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity

“…5D and 8C ). It would now be interesting to validate in vivo whether a combination of a BOS inhibitor and a more potent/selective TMPRSS2 inhibitor ( 68 ) together with hydroxychloroquine ( 44 , 69 ) would synergize the antiviral effect of these entry inhibitors.…”

Fatal Neurodissemination and SARS-CoV-2 Tropism in K18-hACE2 Mice Is Only Partially Dependent on hACE2 Expression

“…Lethal CNS invasion, combined with the absence of severe pulmonary hallmarks associated with lethal COVID-19, therefore calls for attentive caution when utilizing the K18-hACE2 mouse model to investigate certain aspects of SARS-CoV-2 pulmonary pathogenesis. Furthermore, due to the acute and fulminant neuroinvasion and dissemination, the protective ability of certain anti-viral therapies, and T-cell based vaccines against lethal challenge in this model might indeed be underestimated, which is reflected in several studies that have utilized terminal timepoints preceding neuroinvasion as their efficacy endpoints [ 67 , 68 , 69 ]. Regardless, the K18-hACE2 mouse model represents a promising model for understanding the mechanisms governing SARS-CoV-2 neuroinvasion, neurodissemination, and evaluating potent and fast-acting prophylactic countermeasures.…”

Decreased thalamo-cortico connectivity during an implicit sequence motor learning task and 7 days escitalopram intake

“…Given that both the Sequence and Simple Learning conditions reflect motor learning, it is possible that the heightened difficulty associated with the Sequence Learning condition may draw on other domains not related to motor learning, such as attention, heightened visual perception, and general cognitive strategizing. The SPFT, however, was designed to exhibit a minimal learning effect for the Simple Learning condition, and recent preliminary findings have shown differentiated functional connectivity patterns when comparing these conditions at rest 63 , suggesting a distinction in the neural processing of each condition. Secondly, we also cannot rule out generalized SSRI effects that may be unrelated to the task.…”