Mechanism of action articles from across Nature Portfolio

Chemical approaches, such as those that leverage induced proximity, targeted degradation, synthetic gene regulators or protein design offer opportunities to therapeutically target cellular processes that have long been thought of as undruggable. We report on the progress and the potential for transformative collaborations between fields discussed at the 2023 Bringing Chemistry to Medicine symposium at St. Jude Children’s Research Hospital.

Chemogenetic profiling can reveal genetic determinants that coordinate phenotypic responses to therapeutics, along with predicting potential pathways of resistance. A new analytical method for evaluating chemogenetic profiles reveals contributions from death-regulatory genes.

NanoLuciferase- and HaloTag-based screening technologies are versatile tools suitable for the live-cell analysis of the entire small-molecule-induced degradation cascade to uncover the mode of action of proximity-inducing compounds such as PROTACs.

Exportin-1 (XPO1) was identified as the target of small molecules suppressing T cell activation. Selective disruption of the chromatin scaffolding function of XPO1 without blocking nuclear export implicates XPO1 as a target in autoimmunity.

Wenzell et al. developed a massively parallel screening platform to interrogate the sensitivity of signal peptides (SPs) to Sec61 inhibitors. The platform revealed how distinct inhibitors achieve sequence-dependent SP discrimination.

The study of the biomolecular mechanism of action of the isomers trans and cis-[PtI2(ipa)2] (I5 and I6) shows metabolic disruption, ROS generation and senescence. Functionally, I5 reduces tumor growth in vivo without systemic toxicity.

The detailed process of membrane fusion mediated by dynamin-like GTPase atlastin (ATL) remains unclear. Here, authors reveal the conformational dynamics of ATL coupled with GTP hydrolysis cycle at the single molecule level.

Chemical approaches, such as those that leverage induced proximity, targeted degradation, synthetic gene regulators or protein design offer opportunities to therapeutically target cellular processes that have long been thought of as undruggable. We report on the progress and the potential for transformative collaborations between fields discussed at the 2023 Bringing Chemistry to Medicine symposium at St. Jude Children’s Research Hospital.

Chemogenetic profiling can reveal genetic determinants that coordinate phenotypic responses to therapeutics, along with predicting potential pathways of resistance. A new analytical method for evaluating chemogenetic profiles reveals contributions from death-regulatory genes.

The mechanism by which metformin affects food intake remains controversial. Now, two studies link metformin treatment with the induction of the appetite-suppressing metabolite N-lactoyl-phenylalanine, which is produced by the intestine.

Chemically reactive metabolites such as formaldehyde are often toxic and are proposed to react promiscuously with biomolecules. New work shows that some reactive sites on proteins are uniquely sensitive to formaldehyde, leading to functionally important regulation of protein and cell functions.

CAG triple-nucleotide repeats in multiple genes have been linked to various human diseases. A recent study unveils the effects of CAG repeat RNA gelation on protein translation, thereby expanding our knowledge of CAG-elicited toxicities.