Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

Among the plethora of microbial secondary metabolites produced by the soil bacterium of the Streptomyces family is pactamycin, a structurally unique member of aminocyclopentitol-containing natural products (Scheme 1).Pactamycin was isolated in 1961 from a fermentation broth of Streptomyces pactum var pactum by scientists at the former Upjohn Company.[1] It exhibits activity against Grampositive and Gram-negative bacteria, in addition to potent in vitro and in vivo cytotoxic effects.[2] Its further development as a chemotherapeutic agent was curtailed owing to its toxicity. The potent protein synthesis inhibitory activity of pactamycin is attributed to the stage of translocation from the A and P sites to the P and E sites during formation of certain m-RNA-t-RNA complexes in prokaryotes as well as in eukaryotes.[3] Pioneering X-ray crystallographic studies [4] involving binding to the 30S site of Thermus thermophilus show unique interactions, whereby pactamycin adopts a spatial orientation so as to mimic an RNA nucleotide. The two aromatic moieties stack against each other like consecutive RNA bases, while the core cyclopentane motif mimics the RNA sugar-phosphate backbone, which results in an intricate network of hydrogen-bonded interactions within the 30S site of the ribosome. Recent elegant studies on the biosynthesis of pactamycin by Mahmud and coworkers [5a] revealed a gene cluster which also produced pactamycate, de-6-MSA-pactamycin and de-6-MSA-pactamycate, the natural congeners lacking the 6-methyl salicylic acid moiety.

Aldehyde oxidase (AO) catalyzes oxidations of azaheterocycles and aldehydes, amide hydrolysis, and diverse reductions. AO substrates are rare among marketed drugs, and many candidates failed due to poor pharmacokinetics, interspecies differences, and adverse effects. As most issues arise from complex and poorly understood AO biology, an effective solution is to stop or decrease AO metabolism. This perspective focuses on rational drug design approaches to modulate AO‑mediated metabolism in drug discovery. AO biological aspects are also covered, as they are complementary to chemical design and important when selecting the experimental system for risk assessment. The authors’ recommendation is an early consideration of AO-mediated metabolism supported by computational and in vitro experimental methods but not an automatic avoidance of AO structural flags, many of which are versatile and valuable building blocks. Preferably, consideration of AO‑mediated metabolism should be part of the multiparametric drug optimization process, with the goal to improve overall drug-like properties.

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Alkyl- and arylmanganese reagents react with o-chloro or o-bromoaryl ketones to give the substituted ketones in high yields. The cross-coupling reaction is performed under mild conditions (-60 to +40 degrees C, 30 min to 4 h) and takes place with excellent chemoselectivity. [reaction: see text]