From studies on pepsin nearly 200 years ago to the modern pursuit of drugs targeting renin, HIV protease, and βsecretases, aspartic proteases continue to shape the understanding of proteins. Though their structure and reactivity are of great interest for the design of therapeutics, mechanistic details remain elusive. We reveal within a stereoelectronic link between "the most obscure of all the proteases" and the oxyanion hole of serine proteasesthe vivid illustration of nature's catalytic strategy of transition state stabilization. Specifically, rate-limiting breakdown of the tetrahedral intermediate is facilitated by n → π* donation from the forming C-terminus into an active-site glycine. Cooperative H-bonds strengthen this rare, if not unreported, mode of enzyme catalysis in a fashion resembling that found in serine proteases. Exploiting this interaction provides a strategy for the design of next-generation inhibitors.
“Click”
reactions have transformed the molecular
sciences. Augmenting cycloaddition reactions, sulfur(VI) fluoride
exchange (SuFEx) chemistry has diversified the landscape of molecular
assembly. Herein, we report a facile strategy to access SuFExable NH-pyrazoles via strain and catalyst-free 1,3-dipolar cycloadditions
of stabilized diazo compounds under mild conditions. Subsequent SuFEx
proceeds efficiently with various N- and O-nucleophiles. Access to SuFExable NH-pyrazolesa
class of compounds containing two common pharmacophoresenables
future opportunities within drug discovery, chemical biology, materials
chemistry, and related fields.
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