Selective Small Molecule Peptidomimetic Ligands of TrkC and TrkA Receptors Afford Discrete or Complete Neurotrophic Activities

Abstract

We designed a minilibrary of 55 small molecule peptidomimetics based on beta-turns of the neurotrophin growth factor polypeptides neurotrophin-3 (NT-3) and nerve growth factor (NGF). Direct binding, binding competition, and biological screens identified agonistic ligands of the ectodomain of the neurotrophin receptors TrkC and TrkA. Agonism is intrinsic to the peptidomimetic ligand (in the absence of neurotrophins), and/or can also be detected as potentiation of neurotrophin action. Remarkably, some peptidomimetics afford both neurotrophic activities of cell survival and neuronal differentiation, while others afford discrete signals leading to either survival or differentiation. The high rate of hits identified suggests that focused minilibraries may be desirable for developing bioactive ligands of cell surface receptors. Small, selective, proteolytically stable ligands with defined biological activity may have therapeutic potential.

Identification of a Molecular Activator for Insulin Receptor with Potent Anti-diabetic Effects

“…We therefore performed insulin competition assay using flow cytometry (9). CHO-IR cells were incubated with 100 nM FITC-insulin in the presence of DDN at different concentrations.…”

Small, Nonpeptide p75NTRLigands Induce Survival Signaling and Inhibit proNGF-Induced Death

“…Activators of receptors for thrombopoietin (c-Mpl) (Kimura et al, 1998), erythropoietin (Goldberg et al, 2002), insulin (Zhang et al, 1999), and the granulocyte colony stimulating factor (Tian et al, 1998) were identified by empiric, high throughput screening. In addition, Maliartchouk et al (2000a) and Zaccaro et al (2005) have developed low-molecular-weight TrkA agonists through progressive modification of small cyclic peptides emulating a ␤-turn. Virtual (also called in silico) screening of chemical libraries based on the structure of protein-protein interaction sites, ligand-receptor interaction sites, or a series of known small ligands is a potentially powerful approach for the identification of novel lead compounds (for review, see Kurogi and Guner, 2001;Mason et al, 2001;Guner, 2002;Singh et al, 2002;Guner et al, 2004).…”

Selectivity of Cell Signaling in the Neuronal Response Based on NGF Mutations and Peptidomimetics in the Treatment of Alzheimers Disease

“…Cyclized monomeric peptidomimetics designed using the -turn of NT-3 are good TrkC agonists, however some of the peptides showed partial agonistic response towards TrkA. Interestingly, some of the mimetics were able to induce a neurite outgrowth response through TrkA or TrkC, but failed to induce a survival response on TrkA-only expressing cells (Zaccaro et al, 2005). Neurite outgrowth studies were done using PC12 cells which express both TrkA and p75, whereas survival studies were done using TrkA-only expressing 3T3 cells.…”

“…The authors, therefore, argued that this peptidomimetic binds to a special 'hot spot' on TrkA that is accessible only when p75 is co-expressed. The co-expression of p75 with TrkA could result in formation of the TrkA-p75 heteroreceptor complex and binding of p75 to TrkA, perhaps, results in conformational changes in the receptor, making the 'hot spot' accessible (Zaccaro et al, 2005). The D3 mimetic in this series was also tested in cognitively impaired aged rats and showed rescue of the cholinergic phenotype in the cortex and nucleus basilis (Bruno, et al, 2004) and to improve learning and reduce -amyloid in APP mice (Aboulkassim, et al, 2011).…”

“…In other words, will the chemists be able to design sufficient specificity and selectivity into the peptidomimetics to compete with the potential specificity of a 26 kDa neurotrophin protein with its myriad interaction sites? The answer in some cases for selective signaling appears to be yes (Zaccaro et al, 2005;Longo, et al, 2007;Yang et al, 2008). Conversely, will the means of delivery (intracerebroventricular injection, intranasal inhalation, encapsulation) of a full-length neurotrophin mutein be developed sufficiently to make easy administration to the AD brain competitive with a, perhaps, less effective small molecule that is easily delivered?…”