SYNTHESIS OF POTENT ANTAGONISTS FOR THE NATRIURETIC PEPTIDE CLEARANCE RECEPTOR
Objectives: The objective of this research was to design and prepare natriuretic peptide clearance receptor (NPR-C) clearance receptor antagonists with potential therapy for achondroplasia, an autosomal dominant disorder that interferes with the synthesis of the cartilage growth plate of long bones.
Methods: Peptides were synthesized by the standard solid-phase peptide synthesis (SPPS) protocol on Rink resin using the N-Fmoc/t-butyl protection methodology. Biological activity of NPR-C antagonists was assessed using ATDC5 cells.
Results: SPPS rapidly generated many crude compounds with purities exceeding 80%. The synthesized ligands were further purified by liquid chromatography-mass spectrometry (LC-MS), and their identities were confirmed by MS and nuclear magnetic resonance. Ligands with nanomolar potencies were obtained.
Conclusion: Structure-activity relationship studies resulted in a good selection of stable, low nanomolar, and linear NPR-C antagonists.
2. Baxter GF. The natriuretic peptides. Basic Res Cardiol 2004;99(2):71-5.
3. Rose RA, Giles WR. Natriuretic peptide C receptor signalling in the heart and vasculature. J Physiol 2008;586(2):353-66.
4. Thomas G, Moffatt P, Salois P, Gaumond MH, Gingras R, Godin E, et al. Osteocrin, a novel bone-specific secreted protein that modulates the osteoblast phenotype. J Biol Chem 2003;278(50):50563-71.
5. Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 2004;10(1):80-6.
6. Bartels CF, BÃ¼kÃ¼lmez H, Padayatti P, Rhee DK, van Ravenswaaij- Arts C, Pauli RM, et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 2004;75(1):27-34.
7. Amblard M, Fehrentz JA, Martinez J, Subra G. Methods and protocols of modern solid phase Peptide synthesis. Mol Biotechnol 2006;33(3):239-54.
8. Behrendt R, White P, Offer J. Advances in Fmoc solid-phase peptide synthesis. J Pept Sci 2015;22:4-27.
9. Saxena R, Manjan MJ. A thermally responsive short elastin like polypeptide-drug conjugate: Synthesis, characterization and biological evaluation for targeted delivery of anticancer drugs. Int J Pharm Pharm Sci 2014;6:326-33.
10. Anbarasi G, Kumar SK, Narmadha P, Srinivasan N. Effect of Vitamin C on mRNA expression of bmps during fracture healing in the femur callus of Sprague-Dawley female rats. Int J Pharm Pharm Sci 2014;6:208-12.
11. Freidinger RM. Synthesis of Î³-lactam-constrained tryptophyllysine
derivatives. J Org Chem 1985;50:3631-3.
12. Wolfe MS, Dutta D, AubÃ© J. Stereoselective synthesis of freidinger lactams Using oxaziridines derived from amino acids. J Org Chem 1997;62(3):654-63.
13. Veale CA, Alford VC, Aharony D, Banville DL, Bialecki RA, Brown FJ, et al. The discovery of non-basic atrial natriuretic peptide clearance receptor antagonists. Part 1. Bioorg Med Chem Lett 2000;10(17):1949-52.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.