Tehran University of Medical Sciences

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Engineering of a Disulfide Loop Instead of a Zn Binding Loop Restores the Anti-Proliferative, Anti-Angiogenic and Anti-Tumor Activities of the N-Terminal Fragment of Endostatin: Mechanistic and Therapeutic Insights Publisher Pubmed



Chamani R1 ; Asghari SM1 ; Alizadeh AM2 ; Eskandari S1 ; Mansouri K3 ; Khodarahmi R3 ; Taghdir M4 ; Heidari Z1 ; Gorji A5 ; Aliakbar A6 ; Ranjbar B4 ; Khajeh K7
Authors

Source: Vascular Pharmacology Published:2015


Abstract

Although considerable effort has been devoted to understanding the molecular mechanism of endostatin's anti-cancer activity, the role of its Zn bound N-terminal loop has not been completely clarified. To investigate whether Zn binding or the N-terminal loop is involved in the anti-cancer properties of endostatin, we compared the structure and biological activity of a native Zn binding endostatin peptide (ES-Zn) with three variants: a Zn free variant (ES), a variant containing both a Zn binding site and a disulfide bond (ES-SSZn), and a variant including a disulfide loop but incapable of Zn binding (ES-SS). Spectroscopic studies indicated that ES-Zn and ES-SS consist of random coil and β structures, whereas ES-SSZn and ES fold into random coils. Theoretical analysis proposed that ES-Zn and ES-SS have a similar binding site to αVβ3 integrin. The anti-proliferative activity of endostatin was retained by all peptides except ES, and the in vitro anti-angiogenic property was preserved in ES-Zn and ES-SS. Remarkably, breast tumor growth and CD31 activity were inhibited more effectively by ES-SS than by ES-Zn. Therefore, a correlation exists between the N-terminal loop and anti-cancer properties of endostatin fragment and a disulfide loop may be more promising than a Zn binding loop for inhibiting tumor growth. © 2015 Elsevier Inc..