Abstract
Transforming growth factor (TGF)-β1 is a multifunctional protein that is essential in many cellular processes that include fibrosis, inflammation, chondrogenesis, and cartilage repair. In particular, cartilage repair is important to avoid physical disability since this tissue does not have the inherent capacity to regenerate beyond full development. We report here on supramolecular coassemblies of two peptide amphiphile molecules, one containing a TGF-β1 mimetic peptide, and another which is one of two constitutional isomers lacking bioactivity. Using human articular chondrocytes, we investigated the bioactivity of the supramolecular copolymers of each isomer displaying either the previously reported linear form of the mimetic peptide or a novel cyclic analogue. Based on fluorescence depolarization and 1H NMR spin-lattice relaxation times, we found that coassemblies containing the cyclic compound and the most dynamic isomer exhibited the highest intracellular TGF-β1 signaling and gene expression of cartilage extracellular matrix components. We conclude that control of supramolecular motion is emerging as an important factor in the binding of synthetic molecules to receptors that can be tuned through chemical structure.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 21555-21567 |
| Number of pages | 13 |
| Journal | Journal of the American Chemical Society |
| Volume | 146 |
| Issue number | 31 |
| DOIs | |
| State | Accepted/In press - 2024 |
Funding
This research was supported by a gift from Mike and Mary Sue Shannon to Northwestern University for research on musculoskeletal regeneration. Additional support was provided by the Center for Regenerative Nanomedicine at the Simpson Querrey Institute. The authors are grateful to the Peptide Synthesis Core and the Analytical BioNanotechnology Equipment Core of the Simpson Querrey Institute at Northwestern University. These facilities have support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633). The Simpson Querrey Institute, Northwestern University Office for Research, U.S. Army Research Office, and the U.S. Army Medical Research and Materiel Command have also provided funding to develop this facility. Imaging was performed at the Center for Advanced Microscopy (CAM) at Northwestern University, which is supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Solution X-ray experiments were performed at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by Northwestern University, E.I. DuPont de Nemours & Co., and The Dow Chemical Company. Use of APS, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under contract no. DE-AC02-06CH11357. CD was performed at the Northwestern University Keck Biophysics Facility. FTIR was performed at the Integrated Molecular Structure Education and Research Center (IMSERC) at Northwestern University, which has received support from the SHyNE Resource; the State of Illinois; and the IIN. This work also made use of the EPIC and BioCryo facilities of the Northwestern NUANCE center, which has received support from SHyNE Resource (NSF ECCS-1542205); the MRSEC program (NSF DMR-1720139) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois, through the IIN. This study also made use of the Campus Chemical Instrument Center NMR facility at Ohio State University. The authors thank Mark Karver of the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University for his expertise and assistance in PA design and synthesis and Mark Seniw for the design and illustration of schematics in the manuscript. The authors also thank Hiroaki Sai for his assistance in SAXS/WAXS measurements and analysis, Zois Syrgiannis and Peter A. Mirau for their initial NMR experimentation, Alexander L. Hansen for his assistance in DOSY measurements and analysis, and Dhwanit Dave for his preliminary coarse-grained molecular dynamics simulations.
ASJC Scopus subject areas
- Catalysis
- General Chemistry
- Biochemistry
- Colloid and Surface Chemistry