Thrombopoietin Peptide Mimetics

Great attention has been focused on the development of TPO peptide mimetics that activate the TPO receptor (76,77). These mimetics are designed to bind to the TPO receptor but have no sequence homology with endogenous TPO. One is a dimer of two 14-amino acid peptides (AF13948) that has no sequence homology with TPO but

H-lle-Glu-Gly-Pro-Thr-Leu-Arg-Gln-Npa-Leu-Ala- H-lle-Glu-Gly-Pro-Thr-Leu-Arg-Gln-Npa-Leu-Ala-AlaArg-Sar



CH30(CH2CH2Q)nCH2CH 2C-lle-Glu -Gly-Pro-Th r-Leu-Arg-Gln-ivpa-Leu-Ala-

» / CH30(CH2CH2P)nCH2CH2C-lle-Glu-Gly-Pro-Thr-Leu-Arg-Gln-Npa-Leu-Ala-AlaArg-Sär



Fig. 7. The structure of some thrombopoietin peptide mimetics. AF15705 is a peptide dimer composed of two identical 14-amino acid chains linked by a lysine residue and modified to contain two sarcosine (sar) residues. GW395058 is formed by the conjugation of 20,000-Dalton polyethylene glycol to each of the paired peptides. Each of these peptide mimetics stimulates platelet production in mice and is nonimmunogenic. (Reproduced with permission from ref. 77.)

avidly binds and activates the TPO receptor, c-mpl (Fig. 7) (76). Although no longer in clinical development, AF13948 has been modified by amino acid substitution to yield AF15705, which was pegylated to produce GW395058 (77). This peptide mimetic competes with TPO for binding to the TPO receptor but does not elicit neutralizing antibodies (Ab) in mice.

Despite the reduced antigenicity of TPO peptide mimetics, with or without pegyla-tion, recent efforts have focused on the development of nonpeptide, small-molecule mimetics (78-81). These molecules elicit species-specific binding to the TPO receptor, are highly active, and allow for oral administration. Families of hydrazinonaphthalene (Fig. 8), azonaphthalene, semicarbazone, and naphtho[1,2-d]imidazole TPO mimetics have been described. They promote the proliferation of c-mpl-expressing cell lines, produce STAT5 phosphorylation, and stimulate human bone marrow CD34+ cells to mature into CD41+ megakaryocytes. They possess low molecular weights (MW < 500) and median effective concentration (EC50) values of 1-20 nM. Preclinical studies have shown stimulation of platelet production identical with TPO; and human studies may begin soon.

A peptide has been described that binds the EPO receptor at a site distant from the EPO binding site and prevents receptor-ligand internalization, thereby potentiating erythropoiesis (82). An analogous TPO receptor-potentiating peptide has been developed that binds to c-mpl at a location distant from the TPO binding area and may prevent receptor internalization after TPO binding, thereby increasing TPO action. However, after showing no effect in a phase 1 trial, development of this molecule has been suspended.

0 0

Post a comment