Research

Collaboration between Shanghai Institute of Materia Medica, Chinese Academy of Sciences (Prof. Ya-Qiu Long group) and Zhongshan Hospital, Fudan University (Prof. Tongyu Zhu team) afforded a novel class of metabolically stable cyclic peptides which ameliorate kidney ischemia reperfusion injury via a new autophagy mechanism. This finding has been published online this September in the journal of Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (IF: 5.089) (2014, Vol. 1842, Issue 11, Pages 2306–2317). This work was supported by the National Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality.

Kidney ischemia reperfusion (IR) injury is a major cause of delayed graft function and affects both short- and long-term graft survivals in kidney transplantation. But no potent therapy is confirmed thus far. Helix B surface peptide (HBSP), derived from erythropoietin (EPO), displays powerful tissue protection during kidney IR injury without erythropoietic side effects. However, the 2-minute plasma half-life of HBSP restricts its application in vivo.

The researchers employed cyclization strategy for the first time, and synthesized thioether-cyclized helix B peptide (CHBP) to improve metabolic stability and renoprotective effect. CD spectra of the CHBP indicated predominant a-helix conformation. The renoprotective effect of CHBP in terms of renal function, apoptosis, inflammation, extracellular matrix deposition, and histological injury were also detected in vivo and in vitro. Antibody array and western blot were performed to analyze the signal pathway of involvement by CHBP in the IR model and renal tubular epithelial cells. Gratifyingly, CHBP was significantly stable in vivo and in vitro. One dose of 8 nmol/kg CHBP administered intraperitoneally at the onset of reperfusion improved renal protection compared with three doses of 8 nmol/kg linear HBSP in a 48 h murine IR model. In a one-week model, the one dose CHBP-treated group exhibited remarkably improved renal function over the IR group, and attenuated kidney injury, including reduced inflammation and apoptosis. Significantly, the mechanism study demonstrated that CHBP induced autophagy via inhibition of mTORC1 and activation of mTORC2, leading to renoprotective effects on IR. Our results indicate that the novel metabolically stable CHBP is a promising therapeutic medicine for kidney IR injury treatment.

Conformationally constraining of peptides provides an effective approach to tackle the problems of poor cell permeability, secondary structure instability, and in vivo proteolysis, which severely compromise peptides as successful therapeutic agents. Long’s group has made great progresses in this field. They are focused on the structural optimization of endogenous and natural active peptides by stabilizing the secondary structures, thus providing bioavailable therapeutic peptidomimetics (J. Med. Chem. 2008, 51, 6371-6380; J. Med. Chem. 2010, 53, 8376-8386; J. Med. Chem. 2013, 56, 5601-5612; Scientia Sinica Chimica 2013, 43, 1033-1040, cover paper; BBA – Mol. Basis Dis. 2014, 1842, 2306-2317).

Fig. 1. The structures of the cyclic peptides and the plasma stability

Fig. 2. Schematic illustration of the pathway mediated by CHBP. CHBP-induced autophagy is mediated by inhibition of mTORC1 and activation of mTORC2