Synthesis of HDAC Substrate Peptidomimetic Inhibitors Using Fmoc Amino Acids Incorporating Zinc-Binding Groups.

Syntheses of Fmoc amino acids having zinc-binding groups were prepared and incorporated into substrate inhibitor H3K27 peptides using Fmoc/tBu solid-phase peptide synthesis (SPPS). Peptide 11, prepared using Fmoc-Asu(NHOtBu)-OH, is a potent inhibitor (IC50 = 390 nM) of the core NuRD corepressor complex (HDAC1-MTA1-RBBP4). The Fmoc amino acids have the potential to facilitate the rapid preparation of substrate peptidomimetic inhibitor (SPI) libraries in the search for selective HDAC inhibitors

Single-centre prospective cohort study investigating the associations and one-year trends of frailty, cognition, disability and quality of life pre- and post-intervention for chronic limb-threatening ischaemia

Background: Half of people with chronic limb-threatening ischaemia (CLTI) have frailty. This study aimed to describe the associations of frailty with cognition, disability and quality of life (QoL) among CLTI patients over 1 year following surgical or endovascular procedures. Methods: A single-centre prospective cohort study was undertaken. Patients undergoing a procedure for CLTI between May 2019 and May 2021 were eligible (minimum age >65 initially; >50 from November 2019). Participants underwent preoperative assessments for frailty, physical and cognitive function, disability, mood, disease-specific QoL (Vascular QoL questionnaire (VascuQoL)) and generic health-related QoL (EuroQoL EQ-5D-5L). Follow-up was at 3 months (clinic or telephone) and 12 months (telephone). Baseline frailty was assessed using both the Edmonton frail scale (EFS) and the clinical frailty scale (CFS). Frailty during follow-up was re-assessed at 3 and 12 months using the CFS as it can be performed via telephone. Associations of baseline frailty with disability, QoL and mood scores during follow-up were investigated using repeated measures mixed models. Results: Ninety-nine patients completed the baseline assessments. Forty-five (45%) were classified as frail by the EFS. Frailty was associated with a higher prevalence of cognitive impairment based on the Montreal cognitive assessment (52% vs 17%; p<0.001). Eighty-seven patients were eligible for follow-up. Baseline frailty (EFS) was associated with worse QoL scores at all timepoints (VascuQoL p=0.001; EQ-5D-5L p<0.001). Both those with and without frailty at baseline (EFS) had modest improvement in QoL scores at 12 months (VascuQoL p<0.001; EQ-5D-5L p=0.001). Barthel index (disability) scores were lower for those with frailty at baseline (EFS) (p<0.001) and decreased slightly over 12 months for both groups (p=0.007). Five patients (12%) transitioned from frailty to non-frailty at 12 months based on the CFS. However, 10 patients (23%) transitioned from non-frailty to frailty. Conclusions: CLTI patients with frailty have worse QoL and greater disability both pre- and post-intervention. However, they demonstrate similar QoL benefit to those without frailty at 1 year following intervention. Baseline frailty assessment is important to inform prognostic discussions, expectations and shared decision making in CLTI.</p