Creating Diverse Target-Binding Surfaces on FKBP12: Synthesis and Evaluation of a Rapamycin Analogue Library
Open accessAbstract
FK506 and rapamycin are immunosuppressive drugs with a unique mode of action. Prior to binding to their protein targets, these drugs form a complex with an endogenous chaperone FK506-binding protein 12 (FKBP12). The resulting composite FK506-FKBP and rapamycin-FKBP binding surfaces recognize the relatively flat target surfaces of calcineurin and mTOR, respectively, with high affinity and specificity. To test whether this mode of action may be generalized to inhibit other protein targets, especially those that are challenging to inhibit by conventional small molecules, we have developed a parallel synthesis method to generate a 200-member library of bifunctional cyclic peptides as FK506 and rapamycin analogues, which were referred to as "rapalogs". Each rapalog consists of a common FKBP-binding moiety and a variable effector domain. The rapalogs were tested for binding to FKBP12 by a fluorescence polarization competition assay. Our results show that FKBP12 binds to most of the rapalogs with high affinity (K(I) values in the nanomolar to low micromolar range), creating a large repertoire of composite surfaces for potential recognition of macromolecular targets such as proteins.
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- Authors
- Wu, X., Wang, L., Han, Y., Regan, N., Li, P.-K., Villalona, M. A., Hu, X., Briesewitz, R., & Pei, D.
- Affiliations
- The Ohio State University (US)
- University of Toledo (US)
- Corresponding author
- Briesewitz, Roger
- Pei, Dehua
- Venue
- ACS Combinatorial Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-07-28
- Volume
- 13
- Issue
- 5
- Pages
- 486-495
- ISSN
- 2156-8944 (ISSN-L)
- 2156-8952
- PMC
- PMC3171579
- OpenAlex
- W2035919196
- Cited by
- 36
- References
- 33
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 5 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 1 · 2013: 5 · 2012: 2
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Combinatorial Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA132855, R01CA132855)
- National Institute of General Medical Sciences (R01GM062820, GM062820)
- National Institute of Allergy and Infectious Diseases (R01AI062901)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- FKBP12, rapamycin analogs, rapalogs, FK506, cyclic peptides, parallel synthesis, peptide libraries, protein binding affinity, effector domain, immunosuppressants, calcineurin, mTOR
- MeSH terms
- Binding Sites, Models, Molecular, Molecular Conformation, Stereoisomerism, Surface Properties, Sirolimus, Tacrolimus Binding Protein 1A, Small Molecule Libraries, Chemistry Techniques, Synthetic
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