Emerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

Lipocalin-2 (Lcn2) is an innate immune protein elevated by several orders of magnitude in various inflammatory conditions including aging and obesity. Recent studies have shown that Lcn2 is secreted by adipocytes in response to inflammation and is categorized as a new adipokine cross-linking innate immunity and metabolic disorders including obesity. However, the involvement of Lcn2 and its function during the progression of obesity is largely unknown. Recently, browning of white adipose tissue (WAT) has gained attention as a therapeutic strategy to combat obesity. Herein, we have shown that treatment of mature 3T3-L1 adipocytes with recombinant Lcn2 (rec-Lcn2) resulted in the up-regulation of thermogenic and beige/brown markers (UCP1, PRDM16, ZIC-1 and TBX1) and increased mitochondrial activity. Additionally, global Lcn2 genetic knockout (Lcn2KO) mice exhibited accelerated weight gain and visceral fat deposition with age, when compared to wild type (WT) mice. Taken together, both in vitro and in vivo studies suggest that Lcn2 is a naturally occurring adipokine, and may serve as an anti-obesity agent by upregulating the thermogenic markers resulting in the browning of WAT. Therefore, Lcn2 and its downstream signaling pathways could be a potential therapeutic target for obesity. Obesity is a chronic low-grade inflammatory disorder. With nearly 40% of the adult population in the United States being obese, it is no longer just a problem of uncontrolled weight gain but considered as a chronic disease of epidemic proportions. Obesity increases the risk of several disorders, including type-2 diabetes, cardiovascular disease, stroke and bone loss 1. The expense of treating obesity-related illnesses is also increasing and now accounts for nearly 28% of total health-care costs 2. It is estimated that obesity treatment costs between $147 and 210 billion per year, with another $4.3 billion in lost productivity 3-5. Despite the global burden of the disease, there are limited FDA approved anti-obesity drugs available and their use is tempered by significant adverse side effects 6-8. As obesity is now a national epidemic, there is a critical need for the development of anti-obesity drugs with fewer side effects. Adipose tissue plays a vital role in regulating the metabolic disorders and inflammation. White adipose tissue (WAT) primarily functions as an energy storage unit and is a source for inflammatory mediators 9-12. Dysfunction of WAT leads to progression of obesity and its related metabolic disorders 13. Recent studies have shown that conversion of WAT to brown-like beige adipose tissue, known as browning of WAT, is a promising target for the treatment of obesity and associated metabolic and inflammatory disorders 13. Browning of WAT, accompanied by increased mitochondrial activity and thermogenesis, has been reported to decrease weight gain in the high fat diet (HFD) fed obese mouse models 14. More recently, lipocalin 2 (Lcn2) is categorized as a new adipokine secreted by various cell types including adipocytes. It has al...

The most common host entry point of human adapted coronaviruses (CoV) including SARS-CoV-2 is through the initial colonization in the nostril and mouth region which is responsible for spread of the infection. Most recent studies suggest that the commercially available oral and nasal rinse products are effective in inhibiting the viral replication. However, the anti-viral mechanism of the active ingredients present in the oral rinses have not been studied. In the present study, we have assessed in vitro enzymatic inhibitory activity of active ingredients in the oral mouth rinse products: aloin A and B, chlorhexidine, eucalyptol, hexetidine, menthol, triclosan, methyl salicylate, sodium fluoride and povidone, against two important proteases of SARS-CoV-2 PLpro and 3CLpro. Our results indicate only aloin A and B effectively inhibited proteolytic activity of PLpro with an IC50 of 13.16 and 16.08 μM. Interestingly, neither of the aloin isoforms inhibited 3CLpro enzymatic activity. Computational structural modelling of aloin A and B interaction with PLpro revealed that, both aloin isoforms form hydrogen bond with Tyr268 of PLpro, which is critical for their proteolytic activity. Furthermore, 100 ns molecular dynamics (MD) simulation studies predicted that both aloin isoforms have strong interaction with Glu167, which is required for PLpro deubiquitination activity. Our results from the in vitro deubiquitinase inhibition assay show that aloin A and B isomers exhibit deubiquitination inhibitory activity with an IC50 value of 15.68 and 17.51 µM, respectively. In conclusion, the isoforms of aloin inhibit both proteolytic and the deubiquitinating activity of SARS-CoV-2 PLpro, suggesting potential in inhibiting the replication of SARS-CoV-2 virus.