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Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites.
Hosseinzadeh, Parisa; Watson, Paris R; Craven, Timothy W; Li, Xinting; Rettie, Stephen; Pardo-Avila, Fátima; Bera, Asim K; Mulligan, Vikram Khipple; Lu, Peilong; Ford, Alexander S; Weitzner, Brian D; Stewart, Lance J; Moyer, Adam P; Di Piazza, Maddalena; Whalen, Joshua G; Greisen, Per Jr; Christianson, David W; Baker, David.
Afiliação
  • Hosseinzadeh P; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
  • Watson PR; Knight Campus Center, University of Oregon, Eugene, OR, USA.
  • Craven TW; Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
  • Li X; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
  • Rettie S; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
  • Pardo-Avila F; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
  • Bera AK; Molecular and Cellular Biology Ph.D. Program, University of Washington, Seattle, WA, USA.
  • Mulligan VK; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • Lu P; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
  • Ford AS; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
  • Weitzner BD; Systems Biology, Center for Computational Biology, Flatiron Institute, New York, NY, USA.
  • Stewart LJ; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
  • Moyer AP; Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China.
  • Di Piazza M; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
  • Whalen JG; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
  • Greisen PJ; Lyell Immunopharma, Inc., Seattle, WA, USA.
  • Christianson DW; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
  • Baker D; University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
Nat Commun ; 12(1): 3384, 2021 06 07.
Article em En | MEDLINE | ID: mdl-34099674
Despite recent success in computational design of structured cyclic peptides, de novo design of cyclic peptides that bind to any protein functional site remains difficult. To address this challenge, we develop a computational "anchor extension" methodology for targeting protein interfaces by extending a peptide chain around a non-canonical amino acid residue anchor. To test our approach using a well characterized model system, we design cyclic peptides that inhibit histone deacetylases 2 and 6 (HDAC2 and HDAC6) with enhanced potency compared to the original anchor (IC50 values of 9.1 and 4.4 nM for the best binders compared to 5.4 and 0.6 µM for the anchor, respectively). The HDAC6 inhibitor is among the most potent reported so far. These results highlight the potential for de novo design of high-affinity protein-peptide interfaces, as well as the challenges that remain.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos Cíclicos / Relação Estrutura-Atividade / Desenho de Fármacos / Inibidores de Histona Desacetilases Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos Cíclicos / Relação Estrutura-Atividade / Desenho de Fármacos / Inibidores de Histona Desacetilases Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Reino Unido