A novel severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) causing COVID-19 pandemic in humans, recently emerged and has exported in more than 200 countries as a result of rapid spread. In this study, we have made an attempt to investigate the SARS-CoV-2 genome reported from 13 different countries, identification of mutations in major coronavirus proteins of these different SARS-CoV-2 genomes and compared with SARS-CoV. These thirteen complete genome sequences of SARS-CoV-2 showed high identity (>99%) to each other, while they shared 82% identity with SARS-CoV. Here, we performed a very systematic mutational analysis of SARS-CoV-2 genomes from different geographical locations, which enabled us to identify numerous unique features of this viral genome. This includes several important country-specific unique mutations in the major proteins of SARS-CoV-2 namely, replicase polyprotein, spike glycoprotein, envelope protein and nucleocapsid protein. Indian strain showed mutation in spike glycoprotein at R408I and in replicase polyprotein at I671T, P2144S and A2798V,. While the spike protein of Spain & South Korea carried F797C and S221W mutation, respectively. Likewise, several important country specific mutations were analyzed. The effect of mutations of these major proteins were also investigated using various in silico approaches. Main protease (Mpro), the therapeutic target protein of SARS with maximum reported inhibitors, was thoroughly investigated and the effect of mutation on the binding affinity and structural dynamics of Mpro was studied. It was found that the R60C mutation in Mpro affects the protein dynamics, thereby, affecting the binding of inhibitor within its active site. The implications of mutation on structural characteristics were determined. The information provided in this manuscript holds

Emergence of Amphotericin B (AmB) resistant Leishmania donovani has posed major therapeutic challenge against the parasite. Consequently, combination therapy aimed at multiple molecular targets, based on proteome wise network analysis has been recommended. In this regard we had earlier identified and proposed L-asparaginase of Leishmania donovani (LdAI) as a crucial metabolic target. Here we report that both LdAI overexpressing axenic amastigote and promastigote forms of L. donovani survives better when challenged with AmB as compared to wild type strain. Conversely, qRT-PCR analysis showed an upregulation of LdAI in both forms upon AmB treatment. Our data demonstrates the importance of LdAI in imparting immediate protective response to the parasite upon AmB treatment. In the absence of structural and functional information, we modeled LdAI and validated its solution structure through small angle X-ray scattering (SAXS) analysis. We identified its specific inhibitors through ligand and structure-based approach and characterized their effects on enzymatic properties (Km, Vmax, Kcat) of LdAI. We show that in presence of two of the inhibitors L1 and L2, the survival of L. donovani is compromised whereas overexpression of LdAI in these cells restores viability. Taken together, our results conclusively prove that LdAI is a crucial metabolic enzyme conferring early counter measure against AmB treatment by Leishmania.

Acetogenins (ACG) are naturally occurring compounds that are chemically one of the least investigated families. In the review, we have provided a comprehensive listing of 133 of these compounds for which anti-tumor activity has been documented within the literature. We have compiled and studied their chemical structure, in-vitro as well as in-vivo anticancer biological activity. We observed that the relative potency of acetogenins can be categorized as adjacent bis-THF ACGs > nonadjacent bis-THF ACGs > mono-THF ACGs > linear-THF ACGs. Among adjacent bis-THF ACGs, asiminocin (A100), asiminecin (A101), asiminacin (A102) and asimin (A103) are the most active compounds with in-vitro activity (ED50) in the range of 10(-9) to 10(-12) μg/mL. For the nonadjacent bis-THF ACGs, gigantecin (A53) exhibited better cytotoxicity as compared to others in the series with an ED50 in the range of 10(-6) to 10(-8) μg/mL. Similarly, muricatetrocin-C (A36), a mono-THF and coriadienin (A116) a linear ACG has been reported to show promising cytotoxicity with an ED50 of 10(-5) μg/mL. Moreover, in-vivo studies indicate that compounds like bullatacin (A83), desacetyluvaricin (A76), bullatalicin (A58) and annonacin (A8) have demonstrated significant activity in mouse models and thereby exhibiting potential for lead development as a potential anticancer agent/drug. Also, globally oncologists are looking towards compounds from natural origin that inhibits the growth of resistant tumor cells. We find that several acetogenins like bullatacin (A83), motrilin (A95), asimicin (A77), trilobacin (A96), annonacin (A8), gigantetronenin (A108) and squamocin (A73) are efficacious in suppressing the proliferation of the MDR MCF-7/Adr cells. The present analysis suggests that acetogenins can act as yet another important source for obtaining promising lead compounds in order to contribute to cancer prevention, however, in future extensive in-vivo studies in animal models will be needed to provide insight for lead development.

The recent emergence of novel SARS-CoV-2 variants has threatened the efforts to contain the COVID-19 pandemic. The emergence of these “variants of concern” has increased immune escape and has supplanted the ancestral strains. The novel variants harbored by the B.1.617 lineage (kappa and delta) carry mutations within the receptor-binding domain of spike (S) protein (L452R + E484Q and L452R + T478K), the region binding to the host receptor. The double mutations carried by these novel variants are primarily responsible for an upsurge number of COVID-19 cases in India. In this study, we thoroughly investigated the impact of these double mutations on the binding capability to the human host receptor. We performed several structural analyses and found that the studied double mutations increase the binding affinity of the spike protein to the human host receptor (ACE2). Furthermore, our study showed that these double mutants might be a dominant contributor enhancing the receptor-binding affinity of SARS-CoV-2 and consequently making it more stable. We also investigated the impact of these mutations on the binding affinity of two monoclonal antibodies (Abs) (2-15 and LY-CoV555) and found that the presence of the double mutations also hinders its binding with the studied Abs. The principal component analysis, free energy landscape, intermolecular interaction, and other investigations provided a deeper structural insight to better understand the molecular mechanism responsible for increased viral transmissibility of these variants.