Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1 via a comprehensive screening funnel

SAMHD1 is a dNTP triphosphohydrolase governing nucleotide pool homeostasis and can detoxify chemotherapy metabolites controlling their clinical responses. To understand SAMHD1 biology and investigate the potential of targeting SAMHD1 as neoadjuvant to current chemotherapies, we set out to discover selective small-molecule inhibitors. Here, we report a discovery pipeline encompassing a biochemical screening campaign and a set of complementary biochemical, biophysical, and cell-based readouts for rigorous characterization of the screen output. The identified small molecules, TH6342 and analogs, accompanied by inactive control TH7126, demonstrated specific, low μM potency against both physiological and oncology-drug-derived substrates. By coupling kinetic studies with thermal shift assays, we reveal the inhibitory mechanism of TH6342 and analogs, which engage pre-tetrameric SAMHD1 and deter oligomerization and allosteric activation without occupying nucleotide-binding pockets. Altogether, our study diversifies inhibitory modes against SAMHD1, and the discovery pipeline reported herein represents a thorough framework for future SAMHD1 inhibitor development

A review of measurement and modelling results of particle atmosphere–surface exchange

Atmosphere–surface exchange represents one mechanism by which atmospheric particle mass and number size distributions are modified. Deposition velocities (vd) exhibit a pronounced dependence on surface type, due in part to turbulence structure (as manifest in friction velocity), with minima of approximately 0.01 and 0.2 cm s−1 over grasslands and 0.1–1 cm s−1 over forests. However, as noted over 20 yr ago, observations over forests generally do not support the pronounced minimum of deposition velocity (vd) for particle diameters of 0.1–2 μm as manifest in theoretical predictions. Closer agreement between models and observations is found over less-rough surfaces though those data also imply substantially higher surface collection efficiencies than were originally proposed and are manifest in current models. We review theorized dependencies for particle fluxes, describe and critique model approaches and innovations in experimental approaches, and synthesize common conclusions of experimental and modelling studies. We end by proposing a number of research avenues that should be pursued in to facilitate further insights and development of improved numerical models of atmospheric particles