Drug discovery and development articles from across Nature Portfolio

The pore-forming toxin pneumolysin is responsible for the high mortality seen in pneumococcal infections unresponsive to antibiotics. In this work, authors report a small molecule inhibitor targeting pneumolysin and related ones as an anti-virulence strategy protecting human cells during infection.

Isofagomine (IFG) and its analogs have promising glycosidase inhibitory activities, however, a flexible synthetic strategy toward C5a-functionalized IFGs remains to be achieved. Here, the authors show a practical synthesis of C5a-S and R-aminomethyl IFG derivatives via diastereoselective addition of cyanide to cyclic nitrone, and the synthesized derivatives are subsequently assessed for their efficacy as GCase stabilizers.

Installation of small aliphatic motifs within pharmaceuticals provides a medicinally relevant tool in drug discovery programmes. Here, the authors report a late-stage meta-C–H alkylation method facilitating the biological properties modulation of therapeutic agents.

Transfer learning is known to enhance molecular property prediction in limited data sets, however, negative transfer due to insufficient relatedness between source and target tasks continues to be a major challenge. Here, the authors develop a principal gradient-based measurement to evaluate the quantitative transferability from the source property to the target property before applying transfer learning, significantly improving the transfer learning performance.

Fragment-based molecular design uses chemical motifs and combines them into bio-active compounds. While this approach has grown in capability, molecular linker methods are restricted to linking fragments one by one, which makes the search for effective combinations harder. Igashov and colleagues use a conditional diffusion model to link multiple fragments in a one-shot generative process.

A membrane- and DNA-targeting approach is used to design a compound that displays potent activity against multidrug-resistant fungal pathogens without inducing antifungal resistance.

Targeted covalent inhibitors (TCIs) can react irreversibly with lysine in kinases and other proteins. Small molecule TCIs can have both broad or specific lysine targeting whereas peptide- and protein-based TCIs were shown to provide high target specificity for lysines in shallow protein surfaces.

Thomas Kruse and Søren Østergaard reflect on the development of the GLP-1 analogue, semaglutide, which is reshaping peptide therapeutics in type 2 diabetes, weight management, and beyond.

To develop covalent inhibitors with high potency and low off-target effects, combinatorial approaches that search for candidates from large libraries are desired. Here, sulfur(VI) fluoride exchange (SuFEx) in vitro selection is established for the evolution of covalent aptamers from trillions of SuFEx-modified oligonucleotides. Through this technique, covalent aptamers with optimally balanced selectivity and reactivity are identified.

The urgency of finding therapeutic solutions for emerging and existing health challenges has never been more pronounced. In the pursuit of this goal, the value of a strategy that makes use of existing resources is being recognized: drug repurposing or repositioning of compounds for new indications. Such approaches are employed against cancer, rheumatoid arthritis, multiple sclerosis, HIV/AIDS, and many other diseases. This Collection, aptly titled “Drug Repurposing”, includes research and perspectives from scientists at the forefront of this innovative field.

Researchers have found a new route to complex polycyclic indoline structures from indoles and bicyclo[1.1.0]butanes using a Lewis acid catalyst.

Pharmacologically inactive prodrugs that can be activated by near-infrared light are attractive candidates for clinical applications. Now, platinum-based photo-oxidants have been shown to eradicate tumours in mice with a new mode of action.