Amyloid-binding small molecules efficiently block SEVI (semen-derived enhancer of virus infection)- and semen-mediated enhancement of HIV-1 infection.
Semen was recently shown to contain amyloid fibrils formed from a self-assembling peptide fragment of the protein prostatic acid phosphatase. These amyloid fibrils, termed semen-derived enhancer of virus infection, or SEVI, have been shown to strongly enhance HIV infectivity and may play an important role in sexual transmission of HIV, making them a potential microbicide target. One novel approach to target these fibrils is the use of small molecules known to intercalate into the structure of amyloid fibrils, such as derivatives of thioflavin-T. Here, we show that the amyloid-binding small molecule BTA-EG(6) (the hexa(ethylene glycol) derivative of benzothiazole aniline) is able to bind SEVI fibrils and effectively inhibit both SEVI-mediated and semen-mediated enhancement of HIV infection. BTA-EG(6) also blocks the interactions of SEVI with HIV-1 virions and HIV-1 target cells but does not cause any inflammation or toxicity to cervical epithelial cells. These results suggest that an amyloid-binding small molecule may have utility as a microbicide, or microbicidal supplement, for HIV-1.
Olsen
Joanna S
JS
Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14627, USA.
Brown
Caitlin
C
Capule
Christina C
CC
Rubinshtein
Mark
M
Doran
Todd M
TM
Srivastava
Rajesh K
RK
Feng
Changyong
C
Nilsson
Bradley L
BL
Yang
Jerry
J
Dewhurst
Stephen
S
D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003164:Competitive Bidding; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D011485:Protein Binding; D012661:Semen / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry; D014771:Virion / Q000378:metabolism; D053585:Virus Attachment / Q000187:drug effects
D000682:Amyloid; D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T; C005465:benzothiazole