Rapid Peptide Cyclization Inspired by the Modular Logic of Nonribosomal Peptide Synthetases.

Nonribosomal cyclic peptides (NRcPs) are structurally complex natural products and a vital pool of therapeutics, particularly antibiotics. Their structural diversity arises from the ability of the multidomain enzyme assembly lines, nonribosomal peptide synthetases (NRPSs), to utilize bespoke nonproteinogenic amino acids, modify the linear peptide during elongation, and catalyze an array of cyclization modes, e.g., head to tail, side chain to tail. The study and drug development of NRcPs are often limited by a lack of easy synthetic access to NRcPs and their analogues, with selective macrolactamization being a major bottleneck. Herein, we report a generally applicable chemical macrocyclization method of unprecedented speed and selectivity. Inspired by biosynthetic cyclization, it combines the deprotected linear biosynthetic precursor peptide sequence with a highly reactive C-terminus to produce NRcPs and analogues in minutes. The method was applied to several NRcPs of varying sequences, ring sizes, and cyclization modes including rufomycin, colistin, and gramicidin S with comparable success. We thus demonstrate that the linear order of modules in NRPS enzymes that determines peptide sequence encodes the key structural information to produce peptides conformationally biased toward macrocyclization. To fully exploit this conformational bias synthetically, a highly reactive C-terminal acyl azide is also required, alongside carefully balanced pH and solvent conditions. This allows for consistent, facile cyclization of exceptional speed, selectivity, and atom efficiency. This exciting macrolactamization method represents a new enabling technology for the biosynthetic study of NRcPs and their development as therapeutics.

Age-stratified distress thermometers with Worry and Learning problem domains for the paediatric oncology population: Development and validation.

BACKGROUND: The long-term psychological/neuro-psychological sequalae for a minority of survivors of childhood cancer are considerable. This project aims to develop and validate a psychosocial and memory/learning distress thermometer (DT) for paediatric/young adult cancer patients. METHODS: Pilot/Development Age-appropriate versions of the DT were developed. A pilot study tested acceptability, usability, and design. VALIDATION: Seven collaborating paediatric-oncology centres with 549 participants validated the DT against Strengths and difficulties questionnaire (SDQ) and Hospital Anxiety and depression scale (HADS) for psychological issues, Utilities Index Mark 2 (HUI2) for memory/learning issues, PedsQL and SF-8 measured quality of life. RESULTS: Using a cut-off of four, sensitivity against SDQ for under 18 was 75.8%, 18plus against HADS was 94.1%. The specificity was 53.3% against the SDQ for the 18plus specificity against the HADS was 47.1%. The sensitivity against the HUI2 for all age groups was 89.0% specificity was 70.3%. CONCLUSION: The DT is a valid and reliable measure screening instrument. It can be used to identify early on those experiencing psychological distress and memory problems.