De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.

Autor: Roy A; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Shi L; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.; Current Address: Encodia Inc, 5785 Oberlin Drive, San Diego, CA 92121., Chang A; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA., Dong X; Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School, Boston, United States.; Current address: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China; Engineering Research Center of Protein and Peptide Medicine,Ministry of Education., Fernandez A; Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Kraft JC; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Li J; Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School, Boston, United States., Le VQ; Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School, Boston, United States., Winegar RV; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA., Cherf GM; Department of Bioengineering, Stanford University, Stanford CA 94305.; Current Address: Denali Therapeutics, South San Francisco, CA, USA., Slocum D; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA., Daniel Poulson P; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA., Casper GE; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA., Vallecillo-Zúniga ML; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA., Valdoz JC; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA., Miranda MC; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.; Current Address: Department of Medicine Solna, Division of Immunology and Allergy, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden., Bai H; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Kipnis Y; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington., Olshefsky A; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA., Priya T; Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA.; Current Address: Department of Pharmacology, Northwestern University Feinberg School of Medicine; Chicago, IL 60611, USA., Carter L; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Ravichandran R; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Chow CM; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Johnson MR; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Cheng S; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Smith M; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Overed-Sayer C; Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.; Current Address: Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Finch DK; Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.; Current Address: Alchemab Therapeutics Ltd, Cambridge, United Kingdom., Lowe D; Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.; Current Address: Evox Therapeutics Limited, Oxford Science Park, Medawar Centre, East Building, Robert Robinson Avenue, Oxford, OX4 4HG., Bera AK; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Matute-Bello G; Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington., Birkland TP; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington., DiMaio F; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Raghu G; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington., Cochran JR; Department of Bioengineering, Stanford University, Stanford CA 94305., Stewart LJ; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Campbell MG; Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Van Ry PM; Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA., Springer T; Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Departments of Biological Chemistry and Molecular Pharmacology and of Medicine, Harvard Medical School, Boston, United States., Baker D; Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Jun 12. Date of Electronic Publication: 2023 Jun 12.
DOI: 10.1101/2023.06.12.544624
Abstrakt: The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between the two closely related integrin proteins and other RGD integrins, stabilize specific conformational states, and have sufficient stability enabling tissue restricted administration could have considerable therapeutic utility. Existing small molecules and antibody inhibitors do not have all of these properties, and hence there is a need for new approaches. Here we describe a method for computationally designing hyperstable RGD-containing miniproteins that are highly selective for a single RGD integrin heterodimer and conformational state, and use this strategy to design inhibitors of αvβ6 and αvβ8 with high selectivity. The αvβ6 and αvβ8 inhibitors have picomolar affinities for their targets, and >1000-fold selectivity over other RGD integrins. CryoEM structures are within 0.6-0.7Å root-mean-square deviation (RMSD) to the computational design models; the designed αvβ6 inhibitor and native ligand stabilize the open conformation in contrast to the therapeutic anti-αvβ6 antibody BG00011 that stabilizes the bent-closed conformation and caused on-target toxicity in patients with lung fibrosis, and the αvβ8 inhibitor maintains the constitutively fixed extended-closed αvβ8 conformation. In a mouse model of bleomycin-induced lung fibrosis, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics when delivered via oropharyngeal administration mimicking inhalation, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.
Databáze: MEDLINE