Journal of Biological Chemistry
Volume 283, Issue 48, 28 November 2008, Pages 33375-33383
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Protein Structure and Folding
Design of a Conformationally Defined and Proteolytically Stable Circular Mimetic of Brain-derived Neurotrophic Factor*

https://doi.org/10.1074/jbc.M802789200Get rights and content
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Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of neurotrophic factors. BDNF has long been recognized to have potential for the treatment of a variety of human neurodegenerative diseases. However, clinical trials with recombinant BDNF have yet to yield success, leading to the suggestion that alternative means of harnessing BDNF actions for therapeutic use may be required. Here we describe an approach to create low molecular weight peptides that, like BDNF, promote neuronal survival. The peptides were designed to mimic a cationic tripeptide sequence in loop 4 of BDNF shown in previous studies to contribute to the binding of BDNF to the common neurotrophin receptor p75NTR. The best of these peptides, the cyclic pentapeptide 2 (cyclo(-d-Pro-Ala-Lys-Arg-)), despite being of low molecular weight (Mr 580), was found to be an effective promoter of the survival of embryonic chick dorsal root ganglion sensory neurons in vitro (maximal survival, 68 ± 3% of neurons supported by BDNF). Pentapeptide 2 did not affect the phosphorylation of either TrkB (the receptor tyrosine kinase for BDNF) or the downstream signaling molecule MAPK, indicating that its mechanism of neuronal survival action is independent of TrkB. NMR studies reveal that pentapeptide 2 adopts a well defined backbone conformation in solution. Furthermore, pentapeptide 2 was found to be effectively resistant to proteolysis when incubated in a solution of rat plasma in vitro. These properties of pentapeptide 2 (low molecular weight, appropriate pharmacological actions, a well defined solution conformation, and proteolytic stability) render it worthy of further investigation, either as a template for the further design of neuronal survival promoting agents or as a lead compound with therapeutic potential in its own right.

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The atomic coordinates and NMR data for pentapeptide 2 have been deposited with the Biological Magnetic Resonance Data Bank under accession number 20050.

*

This work was supported in part by the National Health and Medical Research Council of Australia, the Motor Neurone Disease Association of Australia, Calibre Biotechnology Pty. Ltd., and a publication grant from the University of Melbourne. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

1

Recipient of a Melbourne Research Scholarship.

2

Present address: Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes St., Fitzroy, Victoria 3065, Australia.

3

Both authors are directors and shareholders of Calibre Biotechnology Pty. Ltd.