ABSTRACT
We have developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases including TMPRSS2, matriptase and hepsin. TMPRSS2 is a membrane associated protease which is highly expressed in the upper and lower respiratory tract and is utilized by SARS-CoV-2 and other viruses to proteolytically process their glycoproteins, enabling host cell receptor binding, entry, replication, and dissemination of new virion particles. We have previously shown that compound MM3122 exhibited subnanomolar potency against all three proteases and displayed potent antiviral effects against SARS-CoV-2 in a cell-viability assay. Herein, we demonstrate that MM3122 potently inhibits viral replication in human lung epithelial cells and is effective against the XBB.1.5 and EG.5.1 variant of SARS-CoV-2. Further, we have evaluated MM3122 in a mouse model of COVID-19 and have demonstrated that MM3122 administered intraperitoneally (IP) before (prophylactic) or after (therapeutic) SARS-CoV-2 infection had significant protective effects against weight loss and lung congestion, and reduced pathology. Amelioration of COVID-19 disease was associated with a reduction in pro-inflammatory cytokines and chemokines production after SARS-CoV-2 infection. Prophylactic, but not therapeutic, administration of MM3122 also reduced virus titers in the lungs of SARS-CoV-2 infected mice. Therefore, MM3122 is a promising lead candidate small molecule drug for the treatment and prevention of infections caused by SARS-CoV-2 and other coronaviruses.
Subject(s)
Severe Acute Respiratory Syndrome , Weight Loss , COVID-19ABSTRACT
The emergence of SARS-CoV-2 variants with greater transmissibility or immune evasion properties has jeopardized the existing vaccine and antibody-based countermeasures. Here, we evaluated the efficacy of boosting with the protein nanoparticle NVX-CoV2373 or NVX-CoV2540 vaccines containing ancestral or BA.5 S proteins, respectively, in mRNA-immunized pre-immune hamsters, against challenge with the Omicron BA.5 variant of SARS-CoV-2. Serum antibody binding and neutralization titers were quantified before challenge, and viral loads were measured 3 days after challenge. Compared to an mRNA vaccine boost, NVX-CoV2373 or NVX-CoV2540 induced higher serum antibody binding responses against ancestral Wuhan-1 or BA.5 spike proteins, and greater neutralization of Omicron BA.1 and BA.5 variants. One and three months after vaccine boosting, hamsters were challenged with the Omicron BA.5 variant. NVX-CoV2373 and NVX-CoV2540 boosted hamsters showed reduced viral infection in the nasal washes, nasal turbinates, and lungs compared to unvaccinated animals. Also, NVX-CoV2540 BA.5 boosted animals had fewer breakthrough infections than NVX-CoV2373 or mRNA-vaccinated hamsters. Thus, immunity induced by NVX-CoV2373 or NVX-CoV2540 boosting can protect against the Omicron BA.5 variant in the Syrian hamster model.
Subject(s)
Breakthrough Pain , Virus DiseasesABSTRACT
The stem-loop II motif (s2m) is a RNA structural element that is found in the 3' untranslated region (UTR) of many RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Though the motif was discovered over twenty-five years ago, its functional significance is unknown. In order to understand the importance of s2m, we created viruses with deletions or mutations of the s2m by reverse genetics and also evaluated a clinical isolate harboring a unique s2m deletion. Deletion or mutation of the s2m had no effect on growth in vitro, or growth and viral fitness in Syrian hamsters in vivo. We also compared the secondary structure of the 3' UTR of wild type and s2m deletion viruses using SHAPE-MaP and DMS-MaPseq. These experiments demonstrate that the s2m forms an independent structure and that its deletion does not alter the overall remaining 3'UTR RNA structure. Together, these findings suggest that s2m is dispensable for SARS-CoV-2.