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From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer’s disease

DOI: 10.1016/j.cell.2021.11.001 DOI Help

Authors: Alastair J. H. Brown (Sosei-Heptares) , Sophie J. Bradley (Sosei-Heptares; University of Glasgow) , Fiona H. Marshall (Sosei-Heptares) , Giles A. Brown (Sosei-Heptares) , Kirstie A. Bennett (Sosei-Heptares) , Jason Brown (Sosei-Heptares) , Julie E. Cansfield (Sosei-Heptares) , David M. Cross (Sosei-Heptares; Cross Pharma Consulting Ltd) , Chris De Graaf (Sosei-Heptares) , Brian D. Hudson (Sosei-Heptares) , Louis Dwomoh (University of Glasgow) , João M. Dias (Sosei-Heptares) , James C. Errey (Sosei-Heptares) , Edward Hurrell (Sosei-Heptares) , Jan Liptrot (Sosei-Heptares) , Giulio Mattedi (Sosei-Heptares) , Colin Molloy (University of Glasgow) , Pradeep J. Nathan (Sosei-Heptares; University of Cambridge) , Krzysztof Okrasa (Sosei-Heptares) , Greg Osborne (Sosei-Heptares) , Jayesh C. Patel (Sosei-Heptares) , Mark Pickworth (Sosei-Heptares) , Nathan Robertson (Sosei-Heptares) , Shahram Shahabi (Eli Lilly & Co) , Christoffer Bundgaard (Eli Lilly & Co; H. Lundbeck A/S) , Keith Phillips (Eli Lilly & Co) , Lisa M. Broad (Eli Lilly & Co) , Anushka V. Goonawardena (SRI International) , Stephen R. Morairty (SRI International) , Michael Browning (University of Oxford; P1vital) , Francesca Perini (Duke-NUS Medical Schoo) , Gerard R. Dawson (University of Oxford) , John F. W. Deakin (University of Manchester) , Robert T. Smith (Sosei-Heptares) , Patrick M. Sexton (Monash University) , Julie Warneck (Protogenia Consulting Ltd) , Mary Vinson (Sosei-Heptares) , Tim Tasker (Sosei-Heptares) , Benjamin G. Tehan (Sosei-Heptares) , Barry Teobald (Sosei-Heptares) , Arthur Christopoulos (Monash University) , Christopher J. Langmead (Sosei-Heptares; Monash University) , Ali Jazayeri (Sosei-Heptares) , Robert M. Cooke (Sosei-Heptares) , Prakash Rucktooa (Sosei-Heptares) , Miles S. Congreve (Sosei-Heptares) , Malcolm Weir (Sosei-Heptares) , Andrew B. Tobin (University of Glasgow)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Cell , VOL 184 , PAGES 5886 - 5901.e22

State: Published (Approved)
Published: November 2021

Abstract: Current therapies for Alzheimer’s disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936—a potential candidate for the treatment of memory loss in Alzheimer’s disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

Journal Keywords: Alzheimer's disease; G protein coupled receptors; muscarinic receptor; M1 muscarinic acetylcholine receptor; structural based drug design; neurodegeneration; prion disease

Diamond Keywords: Alzheimer's Disease

Subject Areas: Biology and Bio-materials, Medicine, Chemistry

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 30/11/2021 10:14


Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)