PEGylation of the Anorexigenic Peptide Neuromedin U Yields a Promising Candidate for the Treatment of Obesity

摘要

Neuromedin U (NMU) is a highly conserved peptide, widely distributed throughout the body with particular abundance in the central nervous systems (CNS), gastrointestinal and genitourinary tracts. NMU has two high affinity G-protein coupled receptors: NMUR1, which is widely expressed in the peripheral tissues, and NMUR2, which is mainly expressed in the CNS. Originally isolated for its ability to contract uterine smooth muscle, NMU has later been found implicated in many physiological processes, including stress, nociception, immunity, inflammation, blood pressure, feeding and energy homeostasis. The latter role in particular is supported by a wealth of pharmacologic and genetic data [1,2], including the report that acute and chronic central administration of NMU in mice inhibits food intake and increases energy expenditure, and that NMU-deflcient mice are hyperphagic and obese, while transgenic mice overexpressing NMU are lean and hypophagic. In addition, an association has been found between NMU gene variants and obesity in humans [1,2]. While the above literature suggests the potential of NMU as an anti-obesity agent, the typical liabilities of native peptides (proteolytic degradation, rapid renal clearance) preclude its direct use as therapeutic. Derivatization with poly(ethylene)glycol ("PEGylation") has emerged as a promising method to extend circulatory half-life, decrease metabolism and immunogenicity of peptides and proteins [3]. These improvements are correlated with the size of the attached polymer, with larger sizes being more effective. PEGylation however typically reduces the biological activity of the attached molecule, because of steric hindrance preventing access to and/or recognition of the receptor, and this decrease is also correlated with increasing PEG size. In addition, the effect is dependent on the specific site of attachment of the polymer [3]. Overall therefore, development of a PEGylated peptide/protein requires multi-parameter optimization, which is molecule-specific. Here we describe the development of a PEGylated analog of NMU.