title: Oligovalent amyloid-binding agents reduce SEVI-mediated enhancement of HIV-1 infection.
abstract: This paper evaluates the use of oligovalent amyloid-binding molecules as potential agents that can reduce the enhancement of human immunodeficiency virus-1 (HIV-1) infection in cells by semen-derived enhancer of virus infection (SEVI) fibrils. These naturally occurring amyloid fibrils found in semen have been implicated as mediators that can facilitate the attachment and internalization of HIV-1 virions to immune cells. Molecules that are capable of reducing the role of SEVI in HIV-1 infection may, therefore, represent a novel strategy to reduce the rate of sexual transmission of HIV-1 in humans. Here, we evaluated a set of synthetic, oligovalent derivatives of benzothiazole aniline (BTA, a known amyloid-binding molecule) for their capability to bind cooperatively to aggregated amyloid peptides and to neutralize the effects of SEVI in HIV-1 infection. We demonstrate that these BTA derivatives exhibit a general trend of increased binding to aggregated amyloids as a function of increasing valence number of the oligomer. Importantly, we find that oligomers of BTA show improved capability to reduce SEVI-mediated infection of HIV-1 in cells compared to a BTA monomer, with the pentamer exhibiting a 65-fold improvement in efficacy compared to a previously reported monomeric BTA derivative. These results, thus, support the use of amyloid-targeting molecules as potential supplements for microbicides to curb the spread of HIV-1 through sexual contact.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0358, USA.
authors.forename: Christina C
authors.initials: CC
authors.lastname: Capule
authors.forename: Caitlin
authors.initials: C
authors.lastname: Brown
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Olsen
authors.forename: Stephen
authors.initials: S
authors.lastname: Dewhurst
authors.forename: Jerry
authors.initials: J
authors.lastname: Yang
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012661:Semen / Q000737:chemistry*; D053585:Virus Attachment / Q000187:drug effects*
chemical_list: D000682:Amyloid; D000814:Aniline Compounds; D000890:Anti-Infective Agents; D052160:Benzothiazoles; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D019713:Receptors, CCR5; D019718:Receptors, CXCR4