2026

De novo design of miniproteins targeting GPCRs

Muratspahić E, Feldman D, Kim DE, Qu X, Bratovianu AM, Rivera-Sánchez P, Voss JH, Hertz EPT, Jeppesen M, Dimitri F, Sakamoto K, Nallathambi A, Peceli P, Cao J, Cary BP, Belousoff MJ, Keov P, Trinh PNH, Chen Q, Ren Y, Fine J, Mishra S, Dalal A, Sinha S, Banerjee R, Ganguly M, Karuppusamy KV, Sappington I, Schlichthaerle T, Zhang JZ, Pillai A, Coventry B, Mihaljević L, Bauer M, Torres SV, Motmaen A, Lee GR, Tran L, Wang X, Goreshnik I, Vafeados DK, Svendsen JE, Hosseinzadeh P, Lindegaard N, Brandt M, Waltenspühl Y, Deibler K, Deweid L, Bennett A, Schöppe J, Dong T, Yan X, Oostdyk L, Cao W, Anantharaman L, Weisser JJ, Bastlund JF, Bundgaard C, Asuni AA, English JG, Stewart L, Halloran L, Spangler JB, Lieber A, Shukla AK, Sexton PM, Roth BL, Krumm BE, Wootten D, Tate CG, Norn C, Baker D.

Show affiliations
  • Muratspahić E — Department of Biochemistry, University of Washington, Seattle, WA, USA. edinm2@uw.edu.
  • Feldman D — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Kim DE — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Qu X — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Bratovianu AM — BioInnovation Institute, Copenhagen, Denmark.
  • Rivera-Sánchez P — BioInnovation Institute, Copenhagen, Denmark.
  • Voss JH — Skape Bio, Copenhagen, Denmark.
  • Hertz EPT — Skape Bio, Copenhagen, Denmark.
  • Jeppesen M — Skape Bio, Copenhagen, Denmark.
  • Dimitri F — BioInnovation Institute, Copenhagen, Denmark.
  • Sakamoto K — Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Nallathambi A — Skape Bio, Copenhagen, Denmark.
  • Peceli P — Skape Bio, Copenhagen, Denmark.
  • Cao J — Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Cary BP — Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Belousoff MJ — Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Keov P — Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Trinh PNH — Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Chen Q — MRC Laboratory of Molecular Biology, Cambridge, UK.
  • Ren Y — MRC Laboratory of Molecular Biology, Cambridge, UK.
  • Fine J — Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA.
  • Mishra S — Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
  • Dalal A — Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
  • Sinha S — Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
  • Banerjee R — Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
  • Ganguly M — Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
  • Karuppusamy KV — Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA.
  • Sappington I — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Schlichthaerle T — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Zhang JZ — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Pillai A — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Coventry B — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Mihaljević L — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Bauer MS — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Torres SV — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Motmaen A — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Lee GR — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Tran L — Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Wang X — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Goreshnik I — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Vafeados DK — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Svendsen JE — Department of Bioengineering, Knight Campus for Accelerating Scientific Impact, University of Oregon, Eugene, OR, USA.
  • Hosseinzadeh P — Department of Bioengineering, Knight Campus for Accelerating Scientific Impact, University of Oregon, Eugene, OR, USA.
  • Lindegaard N — Novo Nordisk, Måløv, Denmark.
  • Brandt M — Novo Nordisk, Måløv, Denmark.
  • Waltenspühl Y — Novo Nordisk, Måløv, Denmark.
  • Deibler K — Novo Nordisk, Måløv, Denmark.
  • Deweid L — Novo Nordisk, Måløv, Denmark.
  • Bennett A — Novo Nordisk, Måløv, Denmark.
  • Schöppe J — Novo Nordisk, Måløv, Denmark.
  • Dong T — Novo Nordisk Research Centre China, Beijing, China.
  • Yan X — Novo Nordisk Research Centre China, Beijing, China.
  • Oostdyk L — LeadHunter Services, Eurofins DiscoverX, Fremont, CA, USA.
  • Cao W — LeadHunter Services, Eurofins DiscoverX, Fremont, CA, USA.
  • Anantharaman L — LeadHunter Services, Eurofins DiscoverX, Fremont, CA, USA.
  • Weisser JJ — Global Research, H. Lundbeck, Copenhagen, Denmark.
  • Bastlund JF — Global Research, H. Lundbeck, Copenhagen, Denmark.
  • Bundgaard C — Global Research, H. Lundbeck, Copenhagen, Denmark.
  • Asuni AA — Global Research, H. Lundbeck, Copenhagen, Denmark.
  • English JG — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Stewart LJ — Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Halloran L — Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA.
  • Spangler JB — Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA.
  • Lieber A — Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA.
  • Shukla AK — Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
  • Sexton PM — Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Roth BL — Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Krumm BE — Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Wootten D — Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Tate CG — MRC Laboratory of Molecular Biology, Cambridge, UK.
  • Norn C — Department of Biochemistry, University of Washington, Seattle, WA, USA. chris.norn@skape.bio.
  • Baker D — Department of Biochemistry, University of Washington, Seattle, WA, USA.
Open on PubMed ↗Open at publisher ↗PMID 42168559
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G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development1,2, but the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic3-6. Here we describe computational de novo design methods and a high-throughput "receptor diversion" microscopy-based screen for generating GPCR binding miniproteins with high affinity, potency and selectivity. We design miniprotein agonists that activate receptors involved in itch and pain, as well as antagonists that inhibit receptors implicated in cancer, metabolic disorders such as diabetes and obesity, and migraine. Cryo-electron microscopy (cryo-EM) structures of five receptor-bound designs are close to the computational design models. A designed chemokine receptor antagonist mobilizes hematopoietic stem and progenitor cells in vivo at a level comparable to a clinically used drug, with fewer adverse effects.

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