Human endostatin is an endogenous angiogenesis inhibitor, and its ability to modulate tumors vascularization is of great therapeutic interest. The antiangiogenic activity is conserved also in some of its synthetic fragments. Fragment 6-49, in particular, is even more active than full length protein. It covers an endostatin region which shows two phenylalanines unusually exposed on the surface. The effect of the mutation of these residues on fragment 6-49 structure and activity are discussed and compared to those of a similar mutation in full length endostatin. A hypothesis on the fragment active epitope is supported by data from molecular dynamics simulations. (c) 2008 Elsevier B. V. All rights reserved.