title: Inhibition of Chikungunya Virus-Induced Cell Death by Salicylate-Derived Bryostatin Analogues Provides Additional Evidence for a PKC-Independent Pathway.
abstract: Chikungunya virus (CHIKV) has been spreading rapidly, with over one million confirmed or suspected cases in the Americas since late 2013. Infection with CHIKV causes devastating arthritic and arthralgic symptoms. Currently, there is no therapy to treat this disease, and the only medications focus on relief of symptoms. Recently, protein kinase C (PKC) modulators have been reported to inhibit CHIKV-induced cell death in cell assays. The salicylate-derived bryostatin analogues described here are structurally simplified PKC modulators that are more synthetically accessible than the natural product bryostatin 1, a PKC modulator and clinical lead for the treatment of cancer, Alzheimer's disease, and HIV eradication. Evaluation of the anti-CHIKV activity of these salicylate-derived bryostatin analogues in cell culture indicates that they are among the most potent cell-protective agents reported to date. Given that they are more accessible and significantly more active than the parent natural product, they represent new therapeutic leads for controlling CHIKV infection. Significantly, these analogues also provide evidence for the involvement of a PKC-independent pathway. This adds a fundamentally distinct aspect to the importance or involvement of PKC modulation in inhibition of chikungunya virus replication, a topic of recent and growing interest.
authors.affiliation: Departments of Chemistry and Chemical and Systems Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Daryl
authors.initials: D
authors.lastname: Staveness
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven-University of Leuven , B-3000 Leuven, Belgium.
authors.forename: Rana
authors.initials: R
authors.lastname: Abdelnabi
authors.affiliation: Departments of Chemistry and Chemical and Systems Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Near
authors.affiliation: Departments of Chemistry and Chemical and Systems Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven-University of Leuven , B-3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven-University of Leuven , B-3000 Leuven, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Delang
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven-University of Leuven , B-3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: Departments of Chemistry and Chemical and Systems Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wender
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D054713:Bryostatins / Q000737:chemistry* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002646:Chikungunya virus / Q000502:physiology*; D006801:Humans; D015394:Molecular Structure; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D012459:Salicylates / Q000737:chemistry* / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D001688:Biological Products; D054713:Bryostatins; D012459:Salicylates; D011493:Protein Kinase C