BACE1 (beta secretase 1, BACE-1 or BACE) has been a key target for Alzheimer’s disease (AD) for nearly two decades (1). However, there was a major disappointment when the Phase III trials with the Merck inhibitor verubecestat failed unequivocally despite lowering A-beta levels. …
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Hot topic: Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein
The A2A adenosine receptor is densely expressed in dopamine-rich areas of the brain and in the vasculature. It is the target of an adjunct medication for Parkinson’s Disease, istradefylline in Japan, an A2A receptor antagonist. The A2A adenosine receptor is an example…
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Hot topic: Conformational plasticity in the selectivity filter of the TRPV2 ion channel
The TRPV2 ion channel is the less well-characterised relative of the TRPV1 or vanilloid receptor that is activated by capsaicin. TRPV2 channels have many similarities to the TRPV1 channels, in that they are homotetrameric and respond to some of the same…
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Hot topic: 3D structure of the P2X3 receptor bound to a negative allosteric modifier, identifies a binding site that is a target for development of novel therapeutic agents
Negative allosteric modulators (NAMs) are of great interest in drug development because they offer improved scope for the production of receptor antagonists with enhanced subtype-selectivity. Indeed, many NAMs are already on the market or undergoing clinical trials. NAMs act by…
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Hot topic: 3D structures of the closed acid-sensing ion channel (ASIC) shed light on the activation mechanism of these neuronal ion channels
ASICs are potential drug targets of interest. Their activation mechanism has however remained elusive. ASICs are neuronal, proton-gated, sodium-permeable channels that are expressed in the central and peripheral nervous system of vertebrates. They form a subfamily of the Epithelial Na…
Hot topic: Engineered mini G proteins provide a useful tool for studying the activation of GPCRs in living cells
In order to stabilize the GPCR-G protein complex, an agonist must be bound to the receptor and the alpha subunit of the heterotrimer must be in a nucleotide-free state. Ground-breaking work by expert crystallographers made use of so-called mini G…
Hot Topic: Unexplored therapeutic opportunities in the human genome
Contemporary drug discovery is dominated by two related themes. The first of these is target validation upon which the sustainability of pharmaceutical R&D (in both the commercial and academic sectors) crucially depends. The second is the size of the pool of human…
