A Designed Peptidomimetic Agonistic Ligand of TrkA Nerve Growth Factor Receptors

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Vol. 57, Issue 2, 385-391, February 2000

A Designed Peptidomimetic Agonistic Ligand of TrkA Nerve Growth Factor Receptors

Sergei Maliartchouk, Yangbo Feng, Ljubica Ivanisevic, Thomas Debeir, A. Claudio Cuello, Kevin Burgess, and H. Uri Saragovi

Departments of Pharmacology and Therapeutics (S.M., L.I., T.D., A.C.C., H.U.S.), Oncology and the Cancer Center (H.U.S.), McGill University, Montréal, Quebec, Canada H3G 1Y6, and Department of Chemistry (Y.F., K.B.), Texas A&M University, College Station, Texas, 77842.

A proteolytically stable small molecule $beta$ -turn peptidomimetic, termed D3, was identified as an agonist of the TrkA neurotrophinreceptor. D3 binds the Ig-like C2 region of the extracellulardomain of TrkA, competes the binding of another TrkA agonist,affords selective trophic protection to TrkA-expressing cell linesand neuronal primary cultures, and induces the differentiationof primary neuronal cultures. These results indicate that a small $beta$ -turn peptidomimetic can activate a tyrosine kinase neurotrophinreceptor that normally binds a relatively large protein ligand.Agents such as D3 that bind the extracellular domain of Trk receptorswill be useful pharmacological agents to address disorders whereTrk receptors play a role, by targeting populationsselectively.

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