Bivalent Diketopiperazine-based Tropomysin Receptor Kinase C (TrkC) Antagonists

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2010 Jun 15

PMID 20540510

Citations 12

Authors

Jing Liu

Fouad Brahimi

H Uri Saragovi

Kevin Burgess

Affiliations

Soon will be listed here.

Abstract

Bivalent molecules containing two beta-turn mimics with side chains that correspond to hot-spots on the neurotrophin NT-3 were prepared. Binding assays showed the mimetics to be selective TrkC ligands, and biological assays showed one mimetic to be an antagonist of the TrkC receptor.

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References

Pattarawarapan M, Reyes S, Xia Z, Zaccaro M, Saragovi H, Burgess K . Selective formation of homo- and heterobivalent peptidomimetics. J Med Chem. 2003; 46(17):3565-7. DOI: 10.1021/jm034103e. View

Kaplan D, Miller F . Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol. 2000; 10(3):381-91. DOI: 10.1016/s0959-4388(00)00092-1. View

Skaper S . The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors. CNS Neurol Disord Drug Targets. 2008; 7(1):46-62. DOI: 10.2174/187152708783885174. View

Chen D, Brahimi F, Angell Y, Li Y, Moscowicz J, Saragovi H . Bivalent peptidomimetic ligands of TrkC are biased agonists and selectively induce neuritogenesis or potentiate neurotrophin-3 trophic signals. ACS Chem Biol. 2009; 4(9):769-81. PMC: 2756187. DOI: 10.1021/cb9001415. View

Maliartchouk S, Feng Y, Ivanisevic L, Debeir T, Cuello A, Burgess K . A designed peptidomimetic agonistic ligand of TrkA nerve growth factor receptors. Mol Pharmacol. 2000; 57(2):385-91. View

Xie Y, Longo F . Neurotrophin small-molecule mimetics. Prog Brain Res. 2000; 128:333-47. DOI: 10.1016/s0079-6123(00)28030-8. View

LeSauteur L, Cheung N, Lisbona R, Saragovi H . Small molecule nerve growth factor analogs image receptors in vivo. Nat Biotechnol. 1996; 14(9):1120-2. DOI: 10.1038/nbt0996-1120. View

Maliartchouk S, Debeir T, Beglova N, Cuello A, Gehring K, Saragovi H . Genuine monovalent ligands of TrkA nerve growth factor receptors reveal a novel pharmacological mechanism of action. J Biol Chem. 2000; 275(14):9946-56. DOI: 10.1074/jbc.275.14.9946. View

Brahimi F, Malakhov A, Lee H, Pattarawarapan M, Ivanisevic L, Burgess K . A peptidomimetic of NT-3 acts as a TrkC antagonist. Peptides. 2009; 30(10):1833-9. PMC: 2755609. DOI: 10.1016/j.peptides.2009.07.015. View

10.

LeSauteur L, Wei L, Gibbs B, Saragovi H . Small peptide mimics of nerve growth factor bind TrkA receptors and affect biological responses. J Biol Chem. 1995; 270(12):6564-9. DOI: 10.1074/jbc.270.12.6564. View

11.

Pattarawarapan M, Zaccaro M, Saragovi U, Burgess K . New templates for syntheses of ring-fused, C(10) beta-turn peptidomimetics leading to the first reported small-molecule mimic of neurotrophin-3. J Med Chem. 2002; 45(20):4387-90. DOI: 10.1021/jm0255421. View

12.

Xie Y, Tisi M, Yeo T, Longo F . Nerve growth factor (NGF) loop 4 dimeric mimetics activate ERK and AKT and promote NGF-like neurotrophic effects. J Biol Chem. 2000; 275(38):29868-74. DOI: 10.1074/jbc.M005071200. View

13.

Longo F, Manthorpe M, Xie Y, Varon S . Synthetic NGF peptide derivatives prevent neuronal death via a p75 receptor-dependent mechanism. J Neurosci Res. 1997; 48(1):1-17. DOI: 10.1002/(sici)1097-4547(19970401)48:1<1::aid-jnr1>3.0.co;2-k. View

14.

Pollack S, Harper S . Small molecule Trk receptor agonists and other neurotrophic factor mimetics. Curr Drug Targets CNS Neurol Disord. 2003; 1(1):59-80. DOI: 10.2174/1568007023339490. View

15.

OLeary P, Hughes R . Design of potent peptide mimetics of brain-derived neurotrophic factor. J Biol Chem. 2003; 278(28):25738-44. DOI: 10.1074/jbc.M303209200. View

16.

Friedman W, Greene L . Neurotrophin signaling via Trks and p75. Exp Cell Res. 1999; 253(1):131-42. DOI: 10.1006/excr.1999.4705. View

17.

Angell Y, Chen D, Brahimi F, Saragovi H, Burgess K . A combinatorial method for solution-phase synthesis of labeled bivalent beta-turn mimics. J Am Chem Soc. 2007; 130(2):556-65. DOI: 10.1021/ja074717z. View

18.

Zaccaro M, Lee H, Pattarawarapan M, Xia Z, Caron A, LHeureux P . Selective small molecule peptidomimetic ligands of TrkC and TrkA receptors afford discrete or complete neurotrophic activities. Chem Biol. 2005; 12(9):1015-28. DOI: 10.1016/j.chembiol.2005.06.015. View

19.

Bonache M, Herranz R, Garcia-Lopez M, Gonzalez-Muniz R . Entry to new conformationally constrained amino acids. First synthesis of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinone derivatives via an intramolecular N(alpha)-C(alpha)-cyclization strategy. J Org Chem. 2001; 66(10):3538-47. DOI: 10.1021/jo015559b. View

20.

Feng Y, Pattarawarapan M, Wang Z, Burgess K . Solid-phase SN2 macrocyclization reactions to form beta-turn mimics. Org Lett. 2000; 1(1):121-4. DOI: 10.1021/ol990597r. View