title: ADS-J1 inhibits semen-derived amyloid fibril formation and blocks fibril-mediated enhancement of HIV-1 infection.
abstract: Semen-derived enhancer of viral infection (SEVI) is composed of amyloid fibrils that can greatly enhance HIV-1 infectivity. By its cationic property, SEVI promotes viral sexual transmission by facilitating the attachment and internalization of HIV-1 to target cells. Therefore, semen-derived amyloid fibrils are potential targets for microbicide design. ADS-J1 is an anionic HIV-1 entry inhibitor. In this study, we explored an additional function of ADS-J1: inhibition of SEVI fibril formation and blockage of SEVI-mediated enhancement of viral infection. We found that ADS-J1 bound to an amyloidogenic peptide fragment (PAP248-286, comprising amino acids 248 to 286 of the enzyme prostatic acid phosphatase), thereby inhibiting peptide assembly into amyloid fibrils. In addition, ADS-J1 binds to mature amyloid fibrils and antagonizes fibril-mediated enhancement of viral infection. Unlike cellulose sulfate, a polyanion that failed in clinical trial to prevent HIV-1 sexual transmission, ADS-J1 shows no ability to facilitate fibril formation. More importantly, the combination of ADS-J1 with several antiretroviral drugs exhibited synergistic effects against HIV-1 infection in semen, with little cytotoxicity to vaginal epithelial cells. Our results suggest that ADS-J1 or a derivative may be incorporated into a combination microbicide for prevention of the sexual transmission of HIV-1.
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Tianrong
authors.initials: T
authors.lastname: Xun
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Jinquan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Ruizhe
authors.initials: R
authors.lastname: Yu
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Li
authors.affiliation: South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, People's Republic of China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai, People's Republic of China.
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China suiyitan@smu.edu.cn liusw@smu.edu.cn.
authors.forename: Suiyi
authors.initials: S
authors.lastname: Tan
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People's Republic of China suiyitan@smu.edu.cn liusw@smu.edu.cn.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
mesh_terms: D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D009282:Naphthalenesulfonates / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D012661:Semen / Q000737:chemistry*; D014227:Triazines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000682:Amyloid; D019380:Anti-HIV Agents; D009282:Naphthalenesulfonates; D014227:Triazines; C407145:ADS J1