B1 receptor

Have you ever wondered how drugs reach their targets and achieve their function within our bodies? If a drug molecule or a ligand is a message, an inbox is typically a receptor in the cell membrane. One such receptor involved in relaying molecular signals is a G protein-coupled receptor (GPCR). About one-third of existing drugs work by controlling the activation of this protein. Researchers now reveal a new way of activating GPCR by triggering shape changes in the intracellular region of the receptor. This new process can help researchers design drugs with fewer or no side effects. Have you ever wondered how drugs reach their targets and achieve their function within our bodies? If a drug molecule or a ligand is a message, an inbox is typically a receptor in the cell membrane. One such receptor involved in relaying molecular signals is a G protein-coupled receptor (GPCR). About one-third of existing drugs work by controlling the activation of this protein. Japanese researchers now reveal a new way of activating GPCR by triggering shape changes in the intracellular region of the receptor. This new process can help researchers design drugs with fewer or no side effects. If the cell membrane is like an Oreo cookie sandwich, GPCR is like a snake with seven segments traversing in and out of the cookie sandwich surface. The extracellular loops are the inbox for messages. When a message molecule binds to the extracellular side of the receptor, it triggers a shape change activating G proteins and the ß-arrestin protein attached to the intracellular side of the receptor. Like a molecular relay, the information passes downstream and affects various bodily processes. That is how we see, smell, and taste, which are sensations of light, smell, and taste messages. Adverse side effects ensue if drugs acting on GPCRs activate multiple signaling pathways rather than a specific target pathway. That is why drug development focuses on activating specific molecular signal pathways within cells. Activating the GPCR from inside the cell rather than outside the cell could be one way to achieve specificity. But until now, there was no evidence of direct activation of only the intracellular side of GPCRs without the initiations from the extracellular side. A team of researchers headed by Osamu Nureki, a professor at the University of Tokyo, and his lab, discovered a new receptor activation mode of a bone metabolism-related GPCR called human parathyroid hormone type 1 receptor (PTH1R) without signal transduction from the extracellular side. "Understanding the molecular mechanism will enable us to design optimal drugs," says Kazuhiro Kobayashi, a doctoral student and an author of the study. Such a drug offers "a promising treatment for osteoporosis." Kobayashi has been conducting research on bone formation in animal models since he was an undergrad. "Treatments for osteoporosis that target PTH1R require strict dosage, have administrative restrictions, and there aren't yet any better alternatives," he says. That motivated their team to look for better drug design strategies targeting the parathyroid hormone receptor. To understand function through structure, they used cryo-electron microscopy and revealed the 3D structure of the PTH1R and G protein bound to a message molecule. The team synthesized a non-peptide message molecule called PCO371 which binds to the intracellular region of the receptor and interacts directly with G protein subunits. In other words, PCO371 activates the receptor after entering the cell. The PCO371-bound PTH1R structure can directly and stably modulate the intracellular side of PTH1R. And because PCO371 activates only G protein and not ß-arrestin it does not cause side effects. This specificity of its binding and receptor activation mode makes it a suitable candidate for potential small-molecule-based drugs for class B1 GPCRs, like PTH1R, which currently lack oral administrative drug ligands. Such drugs would have reduced adverse effects and burdens on patients as they act on specific molecular pathways. The findings from this study will help "develop new drugs for disorders such as obesity, pain, osteoporosis, and neurological disorders." The study appears in the journal Nature.

Bayer announced a handful of pipeline cuts in its quarterly earnings report last week, as CEO Werner Baumann revealed the quarter “came in soft” compared to last year’s performance. The culls include two Phase II programs, a BDKRB1 receptor antagonist for neuropathic pain, and runcaciguat, in development for chronic kidney disease. The BDKRB1 receptor plays a role in pain perception, and Bayer’s candidate, BAY 2395840, came out of a research alliance with Evotec. The company also said it’s discontinuing a Phase I program studying BAY 2395840 in endometriosis. Unlock this story instantly and join 168,600+ biopharma pros reading Endpoints daily — and it's free.

TORONTO, May 03, 2023 (GLOBE NEWSWIRE) -- Dalriada, a leading Canadian contract research organization specializing in small molecule therapies, announces today that it has strengthened its executive leadership team, appointing Adam Davenport, Ph.D. as its Chief Research & Development Officer (CRDO). Dr. Davenport joins from Evotec and will assume strategic and scientific execution responsibility for all of Dalriada’s programs, as well as its current and future R&D capabilities. Serving most recently as Head of Global Molecular Discovery at Evotec where he spent his whole career, Dr. Davenport is a seasoned drug discovery leader and innovator who brings over 22 years of hands-on life science and partnership organization experience, having contributed to drug candidates and clinical assets through both governance and scientific leadership roles. Dr. Davenport has a strong track record of progressing multiple projects through Discovery into Clinical evaluation and is lead inventor of P2X3R antagonists Eliapixant and Filopixant, achieving Phase 2a PoCs in Persistent Chronic Cough (PCC), and Bradykinin B1R antagonist Fulimetibant, undergoing a Phase 2a study to treat diabetic neuropathic pain (DNP). His expertise spans across modalities, diverse target classes (GPCRs, ion-channels, PPIs, CNS, kinases, enzymes) and therapeutic areas (pain, inflammation, cognition, metabolic, Women’s Health, and respiratory). “I am thrilled to welcome Dr. Davenport to Dalriada as its new CRDO,” said Dr. Diana Kraskouskaya, Dalriada’s CEO and co-founder. “Throughout his outstanding career at Evotec, Dr. Davenport has been at the forefront of drug discovery. He is a renowned chemist and authority in his area of expertise, and we believe his addition to the team will further strengthen our strategies and capabilities, as we strive to become the partner of choice for our biotech partners and clients,” she added. Dalriada’s co-founder & CSO Prof. Patrick Gunning added: “At Dalriada we look forward to leveraging Dr. Davenport’s vast experience and insights gained from over 20 years spent at Evotec, and we are excited that our team and clients will benefit from his expertise in a wide range of modalities and disease areas.” Dr. Davenport commented on his appointment: “I am delighted to join Dalriada, a company purposely built as an agile, co-located, and integrated drug discovery partner, which pioneers its unique TURN-KEYTM model to accelerate the discovery and development journey of high value small molecule therapeutics from concept to IND.” “The company is at the forefront of covalent and other novel small molecule modality drug discovery and combining this with its TURN-KEYTM operational model, provides the flexibility, creativity, and innovation that the biotech and VC sectors need to drive value creation and return on investment.” “As a veteran of the CRO world, I have been hugely impressed by the passion, knowledge, drive, and entrepreneurial spirit of Dalriada’s leadership team. I look forward to working alongside them to collectively make a difference for patients, by strategically leading the Company’s R&D.” Dr. Davenport will be based out of Dalriada’s UK site, as part of the Company’s growing presence in Europe, focusing on project strategy and leadership. A detailed biography for Dr. Davenport is available at www.dalriadatx.com/about/adam-davenport/ About Dalriada Drug Discovery Inc. Dalriada, through its TURN-KEY™ Drug Discovery services model, provides a full suite of drug discovery, medicinal chemistry and intellectual property services for semi-virtual, lean biotechnology clients who focus on developing small molecule therapies. With R&D operations in Mississauga, Canada, Dalriada builds focused teams with expertise in MedChem, Biology and ADME to allow for the most rapid and cost-effective project execution and value building. Dalriada has niche expertise in several areas including covalent drug discovery, GPCR programs, targeted protein degradation, novel hetero-bifunctional modalities and CNS programs, with proprietary screening platforms in several of these areas. About Dalriada’s TURN-KEY model TURN-KEYTM provides a powerful one-stop alternative to the prevailing CRO models, fulfilling the most common needs of small to medium-size biotech companies. Via its three key operational pillars of Discovery Labs, Discovery Strategy and Discovery Management, the model reduces the costs of internal R&D and G&A, shortens the timelines to reaching value inflection points, and removes the burden of managing a network of sub-contractors. Our partners instantaneously tap into deep expertise in small molecule discovery (including a curated network of global Key Opinion Leaders), agile execution in integrated lab, and subcontracting and project management teams. The model is fundamentally based on agility, collaborative approach, focus on building value, expert input, and quality execution. A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/0dc99ed0-3885-4f79-9b33-12e7d9c075ae