Human Chorionic Gonadotropin: A Model Molecule For Oligopeptide-Based Drug Discovery

Nisar      Ahmed Khan; Robbert      Benner

Abstract

Small degradation products of proteins can have regulatory powers in biological systems. We have studied the role of selected oligopeptides derived from the pregnancy hormone human chorionic gonadotropin (hCG) in several (patho)physiological systems. The employed oligopeptides (3 up to 7 amino acids) were designed according to the known nick sites in ‘loop-2’ of β-hCG. These oligopeptides can inhibit severe inflammation, the onset of type I diabetes, renal failure and tumorigenesis. One of the oligopeptides (AQGV) appeared capable of accelerating recuperation after lethal radiation of mice, thereby reducing the number of deaths among the irradiated mice. This particular oligopeptide has already been successfully tested in human Phase I and IIa studies. Regulating oligopeptides are not only released as a specific subset by degradation of the pregnancy hormone hCG, but also during the degradation of other body proteins and possibly also by transcription of so-called ‘non-coding’ mRNA. Based on a systems biology approach we designed a series of oligopeptides with particular physico-chemical properties based on the primary structure of β-catenin and C-reactive protein (CRP). Several of the designed oligopeptides were able to inhibit vital genes involved in cell division in a plant model. We call such oligopeptides with regulating activity ‘peptide- i’ peptides, referring to their ability to interfere with the expression of particular genes, and thus with the expression of the related biological activities. The fact that the selected oligopeptides can inhibit the multiplication of plant cells suggests that these peptides, through evolution, are part of a hitherto unknown conserved regulatory system. Based on the data presented we foresee the development of many new regulatory oligopeptide-based pharmaceuticals, which could be a serious option for addressing new therapeutic challenges.

Keywords: hCG, immunoregulation, oligopeptides, peptide-i, pregnancy hormone, protein degradation, regulatory oligopeptide, drugs, Th2 phenomenon, human chorionic gonadotropin, trophoblastic tumor, heterodimeric hCG