Computational Approaches to Discover Novel Natural Compounds for SARS-CoV-2 Therapeutics.

Scientists all over the world are facing a challenging task of finding effective therapeutics for the coronavirus disease (COVID-19). One of the fastest ways of finding putative drug candidates is the use of computational drug discovery approaches. The purpose of the current study is to retrieve natural compounds that have obeyed to drug-like properties as potential inhibitors. Computational molecular modelling techniques were employed to discover compounds with potential SARS-CoV-2 inhibition properties. Accordingly, the InterBioScreen (IBS) database was obtained and was prepared by minimizing the compounds. To the resultant compounds, the absorption, distribution, metabolism, excretion and toxicity (ADMET) and Lipinski's Rule of Five was applied to yield drug-like compounds. The obtained compounds were subjected to molecular dynamics simulation studies to evaluate their stabilities. In the current article, we have employed the docking based virtual screening method using InterBioScreen (IBS) natural compound database yielding two compounds has potential hits. These compounds have demonstrated higher binding affinity scores than the reference compound together with good pharmacokinetic properties. Additionally, the identified hits have displayed stable interaction results inferred by molecular dynamics simulation results. Taken together, we advocate the use of two natural compounds, STOCK1N-71493 and STOCK1N-45683 as SARS-CoV-2 treatment regime.

IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing.

Cross-presentation allows antigen-presenting cells to present exogenous antigens to CD8(+) T cells, playing an essential role in controlling infections and tumor development. IFN-α induces the rapid differentiation of human mono-cytes into dendritic cells, known as IFN-DCs, highly efficient in mediating cross-presentation, as well as the cross-priming of CD8(+) T cells. Here, we have investigated the mechanisms underlying the cross-presentation ability of IFN-DCs by studying the intracellular sorting of soluble ovalbumin and nonstructural-3 protein of hepatitis C virus. Our results demonstrate that, independently from the route and mechanism of antigen entry, IFN-DCs are extraordinarily competent in preserving internalized proteins from early degradation and in routing antigens toward the MHC class-I processing pathway, allowing long-lasting, cross-priming capacity. In IFN-DCs, both early and recycling endosomes function as key compartments for the storage of both antigens and MHC-class I molecules and for proteasome- and transporter-associated with Ag processing-dependent auxiliary cross-presentation pathways. Because IFN-DCs closely resemble human DCs naturally occurring in vivo in response to infections and other danger signals, these findings may have important implications for the design of vaccination strategies in neoplastic or chronic infectious diseases.

R-1626, a specific oral NS5B polymerase inhibitor of hepatitis C virus.

Roche Holding AG is developing R-1626, an oral nucleoside inhibitor of HCV RNA polymerase. R-1626 has been demonstrated to be well absorbed and rapidly converted to the active component R-1479. The compound has demonstrated a strong capacity to inhibit HCV replication in vitro and in vivo, without the rapid development of viral resistance. After 4 weeks of treatment with R-1626 in combination with PEG-IFN plus ribavirin in treatment-naïve patients with genotype 1 HCV infection, HCV RNA could no longer be detected in approximately 74% of patients, compared with 5% of patients treated with PEG-IFN plus ribavirin alone, indicating the high potency of R-1626 to induce HCV RNA viral load reductions. R-1626 was generally well tolerated, although severe side effects of neutropenia were observed at high doses. A phase IIb clinical trial was ongoing at the time of publication to test the efficacy of R-1626 in combination with a standard or lower dose of PEG-IFN and ribavirin in HCV genotype 1-infected patients. Given its potent antiviral effect with an apparent high genetic barrier, R-1626 represents an important advancement in improving the outcome of patients with chronic HCV infection.

SAR and pharmacokinetic studies on phenethylamide inhibitors of the hepatitis C virus NS3/NS4A serine protease.

SAR on the phenethylamide 1 (Ki 1.2 microM) in the P2- and the P'-position led to potent inhibitors, one of which showed good exposure and low clearance when administered intramuscularly to rat.