Affiliation:
1. Institute of Special Environmental Medicine, Nantong University, No. 9, Seyuan Road, Nantong City 226000, Jiangsu Province, P. R. China
2. Contrebola Institute of Computational Interstructural Biophysics, No. 23, Fuxing East Road Nantong City 226000, Jiangsu Province, P. R. China
Abstract
Recombinant tissue-type plasminogen activator (rt-PA, alteplase) is an FDA-approved thrombolytic drug. Designing rt-PA analogs to suppress its inhibition by plasminogen activator inhibitor-1 (PAI-1) without compromising its pharmacological activity has been a continued effort because rt-PA is rapidly inactivated by endogenous PAI-1, leading to the thrombolytic activity of rt-PA being trapped by endogenous PAI-1. Here, incorporating currently available structure of the rt-PA-PAI-1 Michaelis complex structures, this paper uncovers the interstructural biophysics underlying the rt-PA-PAI-1 binding interface, and puts forward a structural biophysical basis for the design of a previously reported rt-PA analogue (T103N, N117Q, KHRR (296-299) AAAA). In addition, this paper proposes a set of rt-PA analogs with lower or higher affinity to PAI-1, including rt-PA (alanine scanning for E_60A, D_189 and R_39), rt-PA (Q60E) and rt-PA (Q60E-F150H-Y151K), towards the release of the trapped thrombolytic activity of rt-PA, and also in the hope that there is still room for the improvement of the efficacy-safety balance of rt-PA in future.
Publisher
World Scientific Pub Co Pte Ltd
Subject
General Earth and Planetary Sciences,General Environmental Science