Influence of Configuration at the 4- and 6-Positions on the Conformation and Anomeric Reactivity and Selectivity of 7-Deoxyheptopyranosyl Donors: Discovery of a Highly Equatorially Selective l-glycero-d-gluco-Heptopyranosyl Donor.

The preparation of four per-O-benzyl-d- or l-glycero-d-galacto and d- or l-glycero-d-gluco heptopyranosyl sulfoxides and the influence of their side-chain conformations on reactivity and stereoselectivity in glycosylation reactions are described. The side-chain conformation in these donors is determined by the relative configuration of its point of attachment to the pyranoside ring and the two flanking centers in agreement with a recent model. In the d- and l-glycero-d-galacto glycosyl donors, the d-glycero-d-galacto isomer with the more electron-withdrawing trans,gauche conformation of its side chain was the more equatorially selective isomer. In the d- and l-glycero-d-gluco glycosyl donors, the l-glycero-d-gluco isomer with the least disarming gauche,gauche side-chain conformation was the most equatorially selective donor. Variable temperature NMR studies, while supporting the formation of intermediate glycosyl triflates at -80 °C in all cases, were inconclusive owing to a change in the decomposition mechanism with the change in configuration. It is suggested that the equatorial selectivity of the l-glycero-d-gluco isomer arises from H-bonding between the glycosyl acceptor and O6 of the donor, which is poised to deliver the acceptor antiperiplanar to the glycosyl triflate, resulting in a high degree of SN2 character in the displacement reaction.

Exploring Noncovalent Protease Inhibitors for the Treatment of Severe Acute Respiratory Syndrome and Severe Acute Respiratory Syndrome-Like Coronaviruses.

Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a group of betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens from this group along with previous studies illustrating the potential of other subgroup 2b members to transmit to humans has underscored the need for antiviral development against them. Coronaviruses modify the host innate immune response in part through the reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To identify unique or overarching subgroup 2b structural features or enzymatic biases, the PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and structurally evaluated. This evaluation revealed that PLpros from subgroup 2b coronaviruses have narrow substrate specificity for K48 polyubiquitin and ISG15 originating from certain species. The PLpro of BtSCoV-Rf1.2004 was used as a tool alongside PLpro of CoV-1 and CoV-2 to design 30 novel noncovalent drug-like pan subgroup 2b PLpro inhibitors that included determining the effects of using previously unexplored core linkers within these compounds. Two crystal structures of BtSCoV-Rf1.2004 PLpro bound to these inhibitors aided in compound design as well as shared structural features among subgroup 2b proteases. Screening of these three subgroup 2b PLpros against this novel set of inhibitors along with cytotoxicity studies provide new directions for pan-coronavirus subgroup 2b antiviral development of PLpro inhibitors.