Two for the Price of One: Heterobivalent Ligand Design Targeting Two Binding Sites on Voltage-Gated Sodium Channels Slows Ligand Dissociation and Enhances Potency.

Voltage-gated sodium (NaV) channels are pore-forming transmembrane proteins that play essential roles in excitable cells, and they are key targets for antiepileptic, antiarrhythmic, and analgesic drugs. We implemented a heterobivalent design strategy to modulate the potency, selectivity, and binding kinetics of NaV channel ligands. We conjugated µ-conotoxin KIIIA, which occludes the pore of the NaV channels, to an analogue of huwentoxin-IV, a spider-venom peptide that allosterically modulates channel gating. Bioorthogonal hydrazide and copper-assisted azide-alkyne cycloaddition conjugation chemistries were employed to generate heterobivalent ligands using polyethylene glycol linkers spanning 40-120 Å. The ligand with an 80 Å linker had the most pronounced bivalent effects, with a significantly slower dissociation rate and 4-24-fold higher potency compared to those of the monovalent peptides for the human NaV1.4 channel. This study highlights the power of heterobivalent ligand design and expands the repertoire of pharmacological probes for exploring the function of NaV channels.

Assessment of the use of Unna boot in the treatment of chronic venous leg ulcers in adults: systematic review protocol.

INTRODUCTION: Chronic venous insufficiency (CVI) is an anomaly of the normal functioning of the venous system caused by valvular incompetence with or without the obstruction of venous flow. This condition can affect either or both of the superficial and the deep venous systems. Venous dysfunction can even result in congenital or acquired disorders, and its complications include venous leg ulcers (VLUs). The objective of this systematic review is to determine the effectiveness of Unna boot in the treatment of wound healing of VLU by assessing the quality of the available evidence. METHODS AND ANALYSIS: A literature search in PubMed, CINAHL, Scopus, Web of Science, Cochrane Library, BVS/BIREME, Embase, ProQuest, BDTD, Thesis and Dissertation Catalog, Sao Paulo Research Foundation/Thesis and dissertation, OPEN THESIS, A service of the US National Institute of Health, Center for Reviews and Dissemination-University of New York and SciElo published in the last 10 years, the period from January 1999 to March 2019. The review will include primary studies (original), and Controlled Trials or Observational studies (cross-sectional, case-control or longitudinal studies) with VLU. The exclusion will include leg ulceration due to different causes, such as pressure, arterial, diabetic or mixed-aetiology leg ulcers. Data synthesis will be performed using a narrative summary and quantitative analysis. ETHICS AND DISSEMINATION: This systematic review does not require approval by the ethics committee, as individual patient data will not be collected. Dissemination of findings will be through publications in peer-reviewed journals and/or via conference presentations. PROSPERO REGISTRATION NUMBER: CRD42019127947.