A new series of synthesized peptides has been described. These peptides are identical to an extracellular domain of the selected growth factor/hormone receptor and are distant from the ligand-binding site (34,132). This peptide activates the receptor signal transduction pathway in the absence of the natural ligand. Naranda et al. (34) reported on the synthesis of a peptide that activates the EPO receptor domain in the absence of EPO. Furthermore, neither the peptide nor EPO altered the affinity of the other for the receptor; thus the peptide does not bind to the EPO binding site. In vivo activity in this regard was demonstrated in a rodent model of carboplatin-induced anemia. Administration of the EPO receptor peptide, in the absence of exogenously administered EPO, significantly improved the hematocrit value relative to the control cohort.
These investigators have recently synthesized another peptide that binds to a portion of the extracellular domain of the human TPO receptor, c-mpl (Dr. Lennart Olsson, personal communication). As noted with the EPO receptor peptide, this peptide binds to c-mpl elsewhere than at the TPO binding site; therefore peptide and growth factor may act together for additive or synergistic activity. Preclinical experiments in rodent models of chemotherapy-induced thrombocytopenia have shown the TPO receptor peptide to be as efficient as recombinant TPO in enhancing platelet recovery. It was also conveyed that the TPO receptor peptide can act in synergy with administered TPO or with the endogenous TPO released in situ during periods of thrombocytopenia.
These peptides differ from the previously described EPO mimetics and peptide agonists of the TPO receptor c-mpl (29-33). The mimetic peptides bind and compete with the natural ligand for the binding site. In the case of agonists for c-mpl, dimeric peptides were constructed that had greater affinity and potency than the monomeric peptide. The peptide dimer stimulated proliferation of megakaryocyte progenitors and maturation of megakaryocytes from human bone marrow (29).
Recently, a nonpeptidyl small molecule that is capable of activating the G-CSF receptor signal transduction pathway, both in vitro and in vivo, has been reported (133). Tian et al. (133) have described the identification of this molecule (SB247464), which binds to the extracellular domain of the G-CSF receptor that is distinct from the G-CSF binding site. This G-CSF mimic stimulated granulocyte colonies from murine bone marrow and significantly increased neutrophil counts when administered on a daily basis to normal mice.
To the best of our knowledge, these growth factor mimetics and peptide receptor agonists have not been further evaluated in animal models of chemotherapy or radiation-induced myelosuppression.
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