Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease.

The main protease M is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported M inhibitors was the peptidomimetic α-ketoamide , whose cocrystal structure with M paved the way for multiple lead-finding studies. We established structure-activity relationships for the series by modifying residues at the P1', P3, and P4 sites.

Evaluation of Cereblon-Directing Warheads for the Development of Orally Bioavailable PROTACs.

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (), and results of a comprehensive comparative study with analogues containing alternative CRBN-directing warheads.

The Use of MPS in Three Rs and Regulatory Applications: Perspectives From Developers on Stakeholder Responsibilities.

Increasing the use of microphysiological systems (MPS) in Three Rs and regulatory applications is a nuanced but important goal, which would also help increase their scientific impact. There are three distinct and important stakeholder groups that each play a unique role in expediting the use of MPS for regulatory purpose - namely, commercial MPS developers, end-users and regulators. Additionally, non-profit organisations, such as the 3Rs Collaborative (3RsC), can help coordinate these efforts.

The brief executive language screen: sensitivity and specificity in acute to early sub-acute stroke.

Introduction: Propositional language and underlying executive functions can be impaired post-stroke and affect communication and quality of life. Current stroke screening tools are largely tailored to patients with aphasia, being either non-verbal or focussed on core language skills such as naming and repetition. The Brief Executive Language Screening Test (BELS) is a newly developed cognitive screening tool that assesses memory, oral apraxia, core language, as well as propositional language and associated executive functions that can be impacted and overlooked in stroke patients without aphasia.