RT Journal Article
SR Electronic
T1 ADS-J1 Disaggregates Semen-derived Amyloid Fibrils
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 292342
DO 10.1101/292342
A1 J. Li
A1 Z. Yang
A1 H. Liu
A1 Y. Lan
A1 T. Zhang
A1 W. Li
A1 T. Qi
A1 Y. Qiu
A1 L. Li
A1 X Zhou
A1 S. Liu
A1 S. Tan
YR 2018
UL http://biorxiv.org/content/early/2018/03/30/292342.abstract
AB Semen-derived amyloid fibrils, composing SEVI (semen-derived enhancer of viral infection) fibrils and SEM1 fibrils, could remarkably enhance HIV-1 sexual transmission and thus, are potential targets for the development of an effective microbicide. Previously, we found that ADS-J1, apart from being an HIV-1 entry inhibitor, could also potently inhibit seminal amyloid fibrillization and block fibril-mediated enhancement of viral infection. However, the remodeling effects of ADS-J1 on mature seminal fibrils were unexplored. Herein, we investigated the capacity of ADS-J1 to disassemble seminal fibrils and the potential mode of action by applying several biophysical and biochemical measurements, combined with molecular dynamic (MD) simulations. We found that ADS-J1 effectively remodeled SEVI, SEM186-107 fibrils and endogenous seminal fibrils. Unlike epi-gallocatechin gallate (EGCG), a universal amyloid fibril breaker, ADS-J1 disaggregated SEVI fibrils into monomeric peptides, which was independent of oxidation reaction. MD simulations revealed that ADS-J1 displayed strong binding potency to the full-length PAP248-286 via electrostatic interactions, hydrophobic interactions and hydrogen bonds. ADS-J1 might initially bind to the fibrillar surface and then occupy the amyloid core, which eventually lead to fibril disassembly. Furthermore, the binding of ADS-J1 with PAP248-286 might induce conformational changes of PAP248-286. Disassembled PAP248-286 might not be favor to re-aggregate into fibrils. ADS-J1 also exerts abilities to remodel a panel of amyloid fibrils, including Aβ1-42, hIAPP1-37 and EP2 fibrils. ADS-J1 displays promising potential to be a combination microbicide and an effective lead-product to treat amyloidogenic diseases.