Mutations in structural proteins of SARS-CoV-2 and potential implications for the ongoing outbreak of infection in India

SARS-CoV-2 has spread in India very quickly from its first reported case on 30 January 2020 in Thrissur, Kerala. With the drastic increasing number of positive cases around the world WHO raised the importance in the assessment of the risk of spread and understanding genetic modifications that could have occurred in the SARS-CoV-2. Using available genome sequence in NCBI repository from the samples of different locations in India, we identified the regions (hotspots) of the viral genome with high rates of mutation. We analysed four regions of the genome encoding structural proteins Spike (S), Nucleocapsid (N), envelop (E) and Membrane (M) proteins. Through computational biology approach, we identified multiple substitution mutations in S and N proteins whereas there is only one substitution in E protein and none in M protein. We showed most of these amino acid residues are evolutionary conserved. The changes in the conserved residues may have significant implication on the stability of the proteins and subsequent interaction with other elements, which are essential for virus propagation. This provides a basis for a better understanding of the genetic variation in SARS-CoV-2 circulating in the India, which might provide important clues for identifying potential therapeutic targets, development of efficient vaccines, antiviral drugs and diagnostic assays for controlling COVID-19.

Highly Diastereoselective Functionalization of Piperidines by Photoredox Catalyzed C–H Arylation and Epimerization

<div>We report a photoredox catalyzed α-amino C–H arylation reaction of highly substituted piperidine derivatives with electron deficient cyano(hetero)arenes. The scope and limitations of the reaction were explored, with piperidines bearing multiple substitution patterns providing the arylated products in good yields and with high diastereoselectivity. In order to probe the mechanism of the overall transformation, optical and fluorescent spectroscopic methods were used. By employing flash-quench transient absorption spectroscopy, we were able to observe electron transfer processes associated with radical formation beyond the initial excited state Ir(ppy)₃ oxidation. Following the rapid and unselective C–H arylation reaction, a slower epimerization occurs to provide the high diastereomer ratio observed for a large majority of the products. Several stereoisomerically pure products were re-subjected to the reaction conditions, each of which converged to the experimentally observed diastereomer ratios. The observed distribution of diastereomers corresponds to a thermodynamic ratio of isomers based upon their calculated relative energies using density functional theory (DFT).</div>

Highly Diastereoselective Functionalization of Piperidines by Photoredox Catalyzed C–H Arylation and Epimerization

<div>We report a photoredox catalyzed α-amino C–H arylation reaction of highly substituted piperidine derivatives with electron deficient cyano(hetero)arenes. The scope and limitations of the reaction were explored, with piperidines bearing multiple substitution patterns providing the arylated products in good yields and with high diastereoselectivity. In order to probe the mechanism of the overall transformation, optical and fluorescent spectroscopic methods were used. By employing flash-quench transient absorption spectroscopy, we were able to observe electron transfer processes associated with radical formation beyond the initial excited state Ir(ppy)₃ oxidation. Following the rapid and unselective C–H arylation reaction, a slower epimerization occurs to provide the high diastereomer ratio observed for a large majority of the products. Several stereoisomerically pure products were re-subjected to the reaction conditions, each of which converged to the experimentally observed diastereomer ratios. The observed distribution of diastereomers corresponds to a thermodynamic ratio of isomers based upon their calculated relative energies using density functional theory (DFT).</div>

Regiocontrolled Synthesis of 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazines

Synthetic access to 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazines has been achieved in 3–4 steps from commercially available pyrazoles. Optimization of a protected hydroxyethyl group on N1 enabled the regiocontrolled construction of pyrazole-5-aldehydes in high yields; subsequent deprotection and reduction generated fused heterocyclic scaffolds bearing multiple substitution patterns. Moreover, the intermediate pyrazole lactols were shown to be versatile synthetic building blocks.