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ADS-J1 disaggregates semen-derived amyloid fibrils
Li, Jinqing; Yang, Zichao; Liu, Han; Qiu, Mengjie; Zhang, Tingting; Li, Wenjuan; Li, Zhaofeng; Qi, Tao1; Qiu, Yurong1; Li, Lin; Zhou, Xuefeng2; Liu, Shuwen; Tan, Suiyi
AbstractSemen-derived amyloid fibrils, comprising 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, SEM1(86-107) fibrils and endogenous seminal fibrils. Unlike epigallocatechin 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 PAP(248-286) 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 PAP(248-286) might induce conformational changes of PAP(248-286). Disassembled PAP(248-286) might not be favorable to re-aggregate into fibrils. ADS-J1 also exerts abilities to remodel a panel of amyloid fibrils, including A beta(1-42), hIAPP(1-37) and EP2 fibrils. ADS-J1 displays promising potential to be a combination microbicide and an effective lead-product to treat amyloidogenic diseases.
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Document Type期刊论文
Affiliation1.Southern Med Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Screening, Guangzhou 510515, Guangdong, Peoples R China
2.Southern Med Univ, Nanfang Hosp, Lab Med Ctr, Guangzhou 510515, Guangdong, Peoples R China
3.Chinese Acad Sci, South China Sea Inst Oceanol, Guangdong Key Lab Marine Mat Med, Key Lab Trop Marine Bioresources & Ecol, Guangzhou 510515, Guangdong, Peoples R China
Recommended Citation
GB/T 7714
Li, Jinqing,Yang, Zichao,Liu, Han,et al. ADS-J1 disaggregates semen-derived amyloid fibrils[J]. BIOCHEMICAL JOURNAL,2019,476:1021, 1035.
APA Li, Jinqing.,Yang, Zichao.,Liu, Han.,Qiu, Mengjie.,Zhang, Tingting.,...&Tan, Suiyi.(2019).ADS-J1 disaggregates semen-derived amyloid fibrils.BIOCHEMICAL JOURNAL,476,1021.
MLA Li, Jinqing,et al."ADS-J1 disaggregates semen-derived amyloid fibrils".BIOCHEMICAL JOURNAL 476(2019):1021.
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