Cyclic peptides can engage a single binding pocket through highly divergent modes.

Cyclic peptide library screening technologies show immense promise for identifying drug leads and chemical probes for challenging targets. However, the structural and functional diversity encoded within such libraries is largely undefined. We have systematically profiled the affinity, selectivity, and structural features of library-derived cyclic peptides selected to recognize three closely related targets: the acetyllysine-binding bromodomain proteins BRD2, -3, and -4. We report affinities as low as 100 pM and specificities of up to 106-fold. Crystal structures of 13 peptide-bromodomain complexes reveal remarkable diversity in both structure and binding mode, including both α-helical and ß-sheet structures as well as bivalent binding modes. The peptides can also exhibit a high degree of structural preorganization. Our data demonstrate the enormous potential within these libraries to provide diverse binding modes against a single target, which underpins their capacity to yield highly potent and selective ligands.

The use of poly-4-hydroxybutyrate (P4HB, Phasix™) mesh in ventral hernia repair: a systematic review and meta-analysis.

PURPOSE/BACKGROUND: Despite the growing use of bioabsorbable mesh in ventral hernia repairs (VHR), the evidence of its impact on patient outcomes remains limited. This study aims to investigate the efficacy and safety profile of poly-4-hydroxybutyrate (P4HB) mesh for ventral hernia repair through a systematic review and meta-analysis. METHODS: A literature search of five databases (PubMed, Embase, Ovid, Medline, and Google Scholar) produced a list of publications that analyzed the use of P4HB mesh in ventral hernia repair in both clean and contaminated cases. The primary postoperative outcomes of hernia recurrence, surgical site infections (SSI), and any complications were analyzed through a pooled meta-analysis. RESULTS: In our systematic review, 21 studies met the inclusion criteria with a total of 1858 patients (933 males and 925 females) and an average age of 56.8 years. The median follow-up ranged from 1.6 to 62.3 months. In our meta-analysis, the use of P4HB mesh in VHR in proportion of events demonstrated a recurrence rate of 9% [6%; 15%], SSI of 10% [6%; 16%] and 35% [9%; 42%] for rate of any complications. Sub-meta-analysis restricted to studies with follow up > 18 months continues to show low rates of recurrence of 9% (95%CI, 4-17%), SSI of 9% (95%CI, 4-16%), and 31% (95%CI, 23-41%) for any complications. CONCLUSION: Our study demonstrates that the use of P4HB mesh is both safe and effective in ventral hernia repairs. When further analyzed past 18 months, the time where P4HB mesh fully resorbs, the rates of hernia recurrence, SSI, and any complications remain low of upwards of 5 years and comparable to the rates seen in synthetic and biologics in similar patient populations.

Hitting a Moving Target: How Does an N-Methyl Group Impact Biological Activity?

Macrocycles have several advantages over small-molecule drugs when it comes to addressing specific protein-protein interactions as therapeutic targets. Herein we report the synthesis of seven new cyclic peptide molecules and their biological activity. These macrocycles were designed to understand how moving an N-methyl moiety around the peptide backbone impacts biological activity. Because the lead non-methylated structure inhibits the oncogenic regulator heat-shock protein 90 (Hsp90), two of the most potent analogues were evaluated for their Hsp90 inhibitory activity. We show that incorporating an N-methyl moiety controls the conformation of the macrocycle, which dramatically impacts cytotoxicity and binding affinity for Hsp90. Thus, the placement of an N-methylated amino acid within a macrocycle generates an unpredictable change to the compound's conformation and hence biological activity.

Clostridium difficile increases the risk for venous thromboembolism.

BACKGROUND: Inflammatory bowel disease is associated with a higher risk for venous thromboembolism (VTE). Whether Clostridium difficile infection similarly increases this risk is unknown. METHODS: This was a retrospective analysis of patients admitted to the surgical intensive care unit (ICU) at the Cedars-Sinai Medical Center from February 2011 to July 2013. The 2 groups were compared using standard statistical methodology. RESULTS: During the 30-month study period, a total of 1,728 patients were admitted to the surgical ICU. A total of 64 patients (3.7%) tested positive for C. difficile. The use of chemical prophylaxis for VTE was significantly higher in the C. difficile group (64.1% vs 46.2%, P = .005). Nonetheless, C. difficile patients had a higher risk for development of a VTE (23.4% vs 11.0%, adjusted odds ratio [95% confidence interval]: 1.87 [1.01 to 3.48], P = .048). In a forward logistic regression model, C. difficile was found to be independently associated with the development of VTE (adjusted odds ratio [95% confidence interval]: 1.87 [1.00 to 3.47], P = .049). CONCLUSIONS: C. difficile infection increases the risk for VTE in surgical patients admitted to the ICU.