Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction.

Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes.

Synthesis of multi-module low density lipoprotein receptor class A domains with acid labile cyanopyridiniumylides (CyPY) as aspartic acid masking groups.

Low-density lipoprotein receptor class A domains (LA modules) are common ligand-binding domains of transmembrane receptors of approximately 40 amino acids that are involved in several cellular processes including endocytosis of extracellular targets. Due to their wide-ranging function and distribution among different transmembrane receptors, LA modules are of high interest for therapeutic applications. However, the efficient chemical synthesis of LA modules and derivatives is hindered by complications, many arising from the high abundance of aspartic acid and consequent aspartimide formation.

Chemical synthesis of a homoserine-mutant of the antibacterial, head-to-tail cyclized protein AS-48 by α-ketoacid-hydroxylamine (KAHA) ligation.

An antibacterial cyclic AS-48 protein was chemically synthesized by α-ketoacid-hydroxylamine (KAHA) ligation. Initial challenges associated with the exceptionally hydrophobic segments arising from the amphiphilic nature of the protein were resolved by the development of bespoke reaction conditions for hydrophobic segments, using hexafluoroisopropanol (HFIP) as a co-solvent. The synthetic protein displays similar biological activity and properties to those of the native protein.

Incorporation of Acid-Labile Masking Groups for the Traceless Synthesis of C-Terminal Peptide α-Ketoacids.

An optimized protocol for the masking of α-ketoacids with acid-labile cyclic acetal protecting groups is reported. Unlike prior approaches, these new conditions allow the synthesis of protected α-ketoacids bearing aromatic, hindered alkyl, and protected polar side chains. Attachment to a Wang-type linker and solid support provides a resin that delivers fully unprotected C-terminal peptide α-ketoacids upon resin cleavage.