title: Simplified Bryostatin Analogues Protect Cells from Chikungunya Virus-Induced Cell Death.
abstract: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus showing a recent resurgence and rapid spread worldwide. While vaccines are under development, there are currently no therapies to treat this disease, except for over-the-counter (OTC) analgesics, which alleviate the devastating arthritic and arthralgic symptoms. To identify novel inhibitors of the virus, analogues of the natural product bryostatin 1, a clinical lead for the treatment of cancer, Alzheimer's disease, and HIV eradication, were investigated for in vitro antiviral activity and were found to be among the most potent inhibitors of CHIKV replication reported to date. Bryostatin-based therapeutic efforts and even recent anti-CHIKV strategies have centered on modulation of protein kinase C (PKC). Intriguingly, while the C ring of bryostatin primarily drives interactions with PKC, A- and B-ring functionality in these analogues has a significant effect on the observed cell-protective activity. Significantly, bryostatin 1 itself, a potent pan-PKC modulator, is inactive in these assays. These new findings indicate that the observed anti-CHIKV activity is not solely mediated by PKC modulation, suggesting possible as yet unidentified targets for CHIKV therapeutic intervention. The high potency and low toxicity of these bryologs make them promising new leads for the development of a CHIKV treatment.
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: Adam J
authors.initials: AJ
authors.lastname: Schrier
authors.affiliation: Departments of Chemistry and Chemical and Systems Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Loy
authors.affiliation: Departments of Chemistry and Chemical and Systems Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Vishal A
authors.initials: VA
authors.lastname: Verma
authors.affiliation: Departments of Chemistry and Chemical and Systems Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Brian A
authors.initials: BA
authors.lastname: DeChristopher
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: 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: D000700:Analgesics / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D054713:Bryostatins / Q000737:chemistry* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D065632:Chikungunya Fever / Q000188:drug therapy*; D002646:Chikungunya virus / Q000502:physiology*; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D004366:Nonprescription Drugs / Q000737:chemistry / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000700:Analgesics; D000998:Antiviral Agents; D054713:Bryostatins; D004366:Nonprescription Drugs; C046785:bryostatin 1; D017868:Cyclic AMP-Dependent Protein Kinases