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For example, the plasma levels of potent bioactive peptides, such as natriuretic peptides and angiotensin II, are usually less than 40 and 20 pg/mL, respectively, which are 10 9 orders of magnitude lower than those of serum albumin and immunoglobulin G. This was primarily due to the unavailability of advanced technology to identify, in human plasma, low-molecular-weight native peptides, which are present at extremely low concentrations and are buried in a vast amount of far larger constituent plasma proteins. In this study, an anorexigenic peptide, ANGT_HUMAN, was identified by exploring cell surface target proteins of the human native peptides identified using plasma peptidomics.ĭespite the anticipation that human plasma contains unidentified, biologically active factors involved in normal human physiology and disease pathophysiology, a limited number of human bioactive peptides have been discovered during the past 2 decades.

Immunoreactive ANGT_HUMAN, distributed throughout human tissues and in human-derived cells, is mostly co-localized with angiotensin II and is occasionally present separately from angiotensin II. Both intraperitoneal and intracerebroventricular injections of low doses of ANGT_HUMAN suppressed spontaneous food and water intake throughout the dark phase of the diurnal cycle without affecting locomotor activity. Because ATP synthase mediates the effects of anorexigenic peptides, the ability of ANGT_HUMAN to modulate eating behavior in mice was investigated. Synthetic fluorescent-labeled and biotinylated ANGT_HUMAN peptides were rendered to bind to cell- and tissue-derived proteins and peptide-cell protein complexes were retrieved and analyzed using liquid chromatography–tandem mass spectrometry, revealing the β-subunit of ATP synthase as its cell-surface binding protein.

A 15-amino-acid residue proangiotensinogen-derived peptide, designated ANGT_HUMAN, elicited cellular responses and bound to cultured human cells.

Using a large number of native peptides previously identified using plasma peptidomics technology, we sequentially synthesized selected sequences and subjected them to functional screening using human cultured cells. The discovery of bioactive peptides is an important research target that enables the elucidation of the pathophysiology of human diseases and provides seeds for drug discovery.