Development of a centralised national AED (automated external defibrillator) network across all ambulance services in the United Kingdom.

Background: Early cardiopulmonary resuscitation and defibrillation is key to increasing survival following an out-of-hospital-cardiac-arrest (OHCA). However, automated external defibrillators (AEDs) are used in a very small percentage of cases. Despite large numbers of AEDs in the community, the absence of a unified system for registering their locations across the UK's ambulance services may have resulted in missed opportunities to save lives. Therefore, representatives from the resuscitation community worked alongside ambulance services to develop a single repository for data on the location of AEDs in the UK. Methods: A national defibrillator network, "The Circuit", was developed by the British Heart Foundation in collaboration with the Association of Ambulance Chief Executives, the UK ambulance services, the Resuscitation Council UK and St John Ambulance. The database allows individuals or organisations to record information about AED location, accessibility, and availability. The database synchronises with ambulance computer aided dispatch systems to provide UK ambulance services with real-time information on the nearest, available AED. Results: The Circuit was successfully rolled out to all 14 UK ambulance services. Since 2019, 82,108 AEDs have been registered. Of the AED data collected by The Circuit, 54% were not previously registered to any ambulance service, and are therefore new registrations. Conclusion: The Circuit provides ambulance services with a single point of access to AED locations in the UK. Since the launch of the system the number of defibrillators registered has doubled. Linking the Circuit data with patient outcome data will help understand whether improving the accessibility to AEDs is associated with increased survival.

The Role of Water Networks in Phosphodiesterase Inhibitor Dissociation and Kinetic Selectivity.

In search of new opportunities to develop Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) inhibitors that have selectivity over the off-target human PDE4 (hPDE4), different stages of a fragment-growing campaign were studied using a variety of biochemical, structural, thermodynamic, and kinetic binding assays. Remarkable differences in binding kinetics were identified and this kinetic selectivity was explored with computational methods, including molecular dynamics and interaction fingerprint analyses. These studies indicate that a key hydrogen bond between GlnQ.50 and the inhibitors is exposed to a water channel in TbrPDEB1, leading to fast unbinding. This water channel is not present in hPDE4, leading to inhibitors with a longer residence time. The computer-aided drug design protocols were applied to a recently disclosed TbrPDEB1 inhibitor with a different scaffold and our results confirm that shielding this key hydrogen bond through disruption of the water channel represents a viable design strategy to develop more selective inhibitors of TbrPDEB1. Our work shows how computational protocols can be used to understand the contribution of solvent dynamics to inhibitor binding, and our results can be applied in the design of selective inhibitors for homologous PDEs found in related parasites.

A Chemical Probe for the Methyl Transferase PRMT5 with a Novel Binding Mode.

Protein arginine methyltransferase 5 (PRMT5) is an enzyme that can symmetrically dimethylate arginine residues in histones and nonhistone proteins by using S-adenosyl methionine (SAM) as the methyl donating cofactor. We have designed a library of SAM analogues and discovered potent, cell-active, and selective spiro diamines as inhibitors of the enzymatic function of PRMT5. Crystallographic studies confirmed a very interesting binding mode, involving protein flexibility, where both the cofactor pocket and part of substrate binding site are occupied by these inhibitors.

Identification and Investigation of Novel Binding Fragments in the Fatty Acid Binding Protein 6 (FABP6).

Fatty acid binding protein 6 (FABP6) is a potential drug discovery target, which, if inhibited, may have a therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors of FABP6, and with the target believed to be amenable to fragment-based drug discovery, a structurally enabled program was initiated. This program successfully identified fragment hits using the surface plasmon resonance (SPR) platform. Several hits were validated with SAR and were found to be displaced by the natural ligand taurocholate. We report the first crystal structure of human FABP6 in the unbound form, in complex with cholate, and with one of the key fragments.

Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1.

The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC(50)s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.

Novel indazole non-nucleoside reverse transcriptase inhibitors using molecular hybridization based on crystallographic overlays.

A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their lack of resilience to mutations in the reverse transcriptase (RT) enzyme. Using structural overlays of the known inhibitors efavirenz and capravirine complexed in RT as a starting point, and structure-based drug design techniques, we have created a novel series of indazole NNRTIs that possess excellent metabolic stability and mutant resilience.