Stabilization of a miniprotein fold by an unpuckered proline surrogate.

The unique role of proline in modulating protein folding and recognition makes it an attractive target for substitution to generate new proteomimetics. The design, synthesis, and conformational analysis of non-canonical surrogates can also aid in parsing the role of prolyl stereoelectronic effects on structure. We recently described the synthesis and conformational analysis of dehydro-δ-azaproline (ΔaPro), a novel unsaturated analogue of proline featuring a planar dehydropyrazine ring.

Synthesis and stability of collagen mimetic peptides featuring δ-heteroatom-substituted prolines.

We describe the first investigation of collagen mimetic peptides harboring proline surrogates with heteroatoms at the δ-position. While dehydro-δ-azaproline and (-methyl)-δ-azaproline destabilized the parent structure, replacement of the Xaa proline residue with δ-oxaproline resulted in a faster-folding collagen mimetic peptide with equivalent thermal stability.

A phase III randomised study of first-line NUC-1031/cisplatin vs. gemcitabine/cisplatin in advanced biliary tract cancer.

Background And Aims: The previous first-line standard of care for advanced biliary tract cancer (aBTC), gemcitabine/cisplatin, had modest efficacy. NUC-1031 is a phosphoramidate modification of gemcitabine. We report final analyses of the NuTide:121 study, designed to compare the efficacy of NUC-1031/cisplatin to gemcitabine/cisplatin in aBTC.

DICER1 in pediatric and adult cancer predisposition populations: prevalence, phenotypes and mosaics.

Purpose: DICER1 tumor predisposition syndrome (DTPS) is a hereditary condition affecting children and young adults. Identification of DICER1 carriers is key for prevention and actionability in families. However, DTPS diagnosis is hindered by its incomplete penetrance and broad phenotypic spectrum.

Pleomorphic effects of three small-molecule inhibitors on transcription elongation by RNA polymerase.

The RNA polymerase (MtbRNAP) is the target of the first-line anti-tuberculosis inhibitor rifampin, however, the emergence of rifampin resistance necessitates the development of new antibiotics. Here, we communicate the first single-molecule characterization of MtbRNAP elongation and its inhibition by three diverse small-molecule inhibitors: N(α)-aroyl-N-aryl-phenylalaninamide (D-IX216), streptolydigin (Stl), and pseudouridimycin (PUM) using high-resolution optical tweezers. Compared to RNA polymerase (EcoRNAP), MtbRNAP transcribes more slowly, has similar mechanical robustness, and only weakly recognizes pause sequences.