AAVogen’s Post

In patients with various forms of transthyretin amyloidosis, including transthyretin amyloid polyneuropathy, a reliable, useful tool for investigating the disease and how to rank drug candidates is X-ray crystallography, according to findings from an analysis published in the journal Molecules MDPI. Read more: https://brnw.ch/21wHO69 #RareDisease

Understanding the roles of individual conformational states in signaling efficacy and bias will help us to design drugs that discriminately target a disease-related conformation. My first BioRxiv manuscript is online, which focuses on determining the structure of the intermediate GPCR-G protein complex and its function in signaling. Guided by a conformational landscape profiled by 19F quantitative NMR (19F-qNMR) and MD, we resolved the first structure of an unliganded GPCR-Gαsβγ intermediate complex with a resolution of 2.8A by a conformational blockade strategy to capture the transient state. More importantly. we presented direct evidence that the intermediate GPCR-G protein complex initiates a rate-limited nucleotide exchange without progressing to the fully activated end-state complex, thereby bridging a critical gap in our understanding the complexity of GPCR signaling, including efficacy and selectivity. https://lnkd.in/eVpM5uaS

Pick of the week from J Med Chem: optimization of LRRK2 inhibitors for Parkinson's disease from Merck (Katie Logan). A story of how to derisk a high efflux series using a properties based approach while leveraging from structure based design to maintain on target potency and selectivity. Some useful insights on building an efflux/CNS penetration characterization funnel. #medchem https://lnkd.in/epG2CHev

Ligand efficacy modulates conformational dynamics of the µ-opioid receptor Nature https://lnkd.in/enqpAXkj

A good day to share the publication of the validation of FoundationOne Tracker, a therapy response ctDNA monitoring assay. https://lnkd.in/ecdQHDBQ

Social Pharma Patient-Centric Marketing socialpharma.net >>> Gene&Cell Therapy >> Meet this year’s Endpoints 11; J&J winds down cardiovascular and metabolic unit; BMS wins schizophrenia approval; and more  #lucidquest #genetherapy #celltherapy

A novel form of conditional CAR-T armouring with IL-18 that only releases the cytokine when CAR-T cells are activated has been published by John Maher and colleagues. This is an elegant solution to the toxicity of constitutive IL-18 release, yet retains constitutive production of IL-18 by substituting the caspase 1 cleavage site within pro-IL18 with that preferred by granzyme B, yielding GzB-IL18. Only when the CAR is active and granzyme is released does the IL-18 become liberated. https://lnkd.in/enZ374BV

Excited to announce our recent publication, highlighting the essential role of ANGPTL8 in insulin signaling and differentiation in pre-adipocytes. Explore the details at https://lnkd.in/eU5MXTAh

Sequential, multistep activation mechanism of metabotropic glutamate receptor subtype 5. Just out. https://lnkd.in/dCaR7J96

Will cannabis help the inflammatory symptoms of #ibs #alzheimers #rheumatoidarthritis #fibromyalgia? Studies show that the CB2 receptor, mainly expressed in immune tissue, is linked to inflammatory responses in the body. And that the CB2 receptor is the peripheral receptor for cannabinoids (Cell Mol Life Sci., 2016; 73(23) 4449-4470) Additionally, researchers have identified that a specific terpene called beta-caryophyllene, which comprises between 12-35 percent of cannabis’s essential oil (depending on the strain), activates the CB2 receptor. What’s important to understand here is that beta-caryophyllene enables the CB2 receptor exclusively, meaning that it doesn’t attach to the CB1 receptor. READ MORE: https://lnkd.in/dsQSK9dP