PYC-35B

Antimelanogenic peptides are potentially useful to treat hyperpigmentation, but many peptides have limited application because of high cost and/or low activity.

To identify small and potent peptide inhibitors of cellular melanin synthesis that are useful for cosmetic and medical applications.

A positional scanning synthetic tetrapeptide combinatorial library was used for screening of potentially active peptides. Antimelanogenic activities of the peptide pools and individual peptides were evaluated in B16-F10 melanoma cells and human epidermal melanocytes treated with alpha-melanocyte-stimulating hormone (α-MSH).

Predicted active tetrapeptide sequences were R-(F/L)-(C/W)-(G/R)-NH₂ . Of the individual tetrapeptides tested, D3 (RFWG-NH₂ ) and D5 (RLWG-NH₂ ) exhibited high antimelanogenic activities. Tetrapeptide D9 (FRWG-NH₂ ) with a sequence identical to that of a portion of α-MSH also showed antimelanogenic activity. Of the tripeptides tested, E5 (FWG-NH₂ ), E6 (LWG-NH₂ ) and E7 (RWG-NH₂ ) were relatively more active. Dipeptide F1 (WG-NH₂ ) and monopeptide G1 (G-NH₂ , glycinamide) retained activity, but G2 (Ac-G-NH₂ ) and G3 (glycine) did not. The antimelanogenic activities of peptides D3, E5, F1 and G1 were verified in α-MSH-stimulated human epidermal melanocytes. Commercially available G-NH₂ ·HCl suppressed the phosphorylation levels of cAMP-responsive element binding protein, protein levels of microphthalmia-associated transcription factor and tyrosinase, l-tyrosine hydroxylase activity of tyrosinase, and the melanin levels in stimulated cells.

Small peptides, including glycinamide and tryptophanyl glycinamide, are potent antimelanogenic agents with potential value for the treatment of skin hyperpigmentation.

Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients who have a variety of underlying pathologies such as chronic kidney disease. Treatment with recombinant human EPO (rHuEPO) at supraphysiologic concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients, and it presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF) 1α and HIF2α control the physiologic response to hypoxia and invoke a program of increased erythropoiesis. Levels of HIFα are modulated by oxygen tension via the action of a family of HIF-prolyl hydroxylases (PHDs), which tag HIFα for proteasomal degradation. Inhibition of these PHDs simulates conditions of mild hypoxia, leading to a potentially more physiologic erythropoietic response and presenting a potential alternative to high doses of rHuEPO. Here we describe the discovery and characterization of GSK1278863 [2-(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido) acetic acid], a pyrimidinetrione-glycinamide low nanomolar inhibitor of PHDs 1-3 that stabilizes HIFα in cell lines, resulting in the production of increased levels of EPO. In normal mice, a single dose of GSK1278863 induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. GSK1278863 significantly increased reticulocytes and red cell mass parameters in preclinical species after once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile, supporting continued clinical development. GSK1278863 is currently in phase 3 clinical trials for treatment of anemia in patients with chronic kidney disease.