Comparative analysis of the anti-chikungunya virus activity of novel bryostatin analogs confirms the existence of a PKC-independent mechanism.
Previously, we reported that salicylate-based analogs of bryostatin protect cells from chikungunya virus (CHIKV)-induced cell death. Interestingly, 'capping' the hydroxyl group at C26 of a lead bryostatin analog, a position known to be crucial for binding to and modulation of protein kinase C (PKC), did not abrogate the anti-CHIKV activity of the scaffold, putatively indicating the involvement of a pathway independent of PKC. The work detailed in this study demonstrates that salicylate-derived analog 1 and two capped analogs (2 and 3) are not merely cytoprotective compounds, but act as selective and specific inhibitors of CHIKV replication. Further, a detailed comparative analysis of the effect of the non-capped versus the two capped analogs revealed that compound 1 acts both at early and late stages in the chikungunya virus replication cycle, while the capped analogs only interfere with a later stage process. Co-dosing with the PKC inhibitors sotrastaurin and Gö6976 counteracts the antiviral activity of compound 1 without affecting that of capped analogs 2 and 3, providing further evidence that the latter elicit their anti-CHIKV activity independently of PKC. Remarkably, treatment of CHIKV-infected cells with a combination of compound 1 and a capped analog resulted in a pronounced synergistic antiviral effect. Thus, these salicylate-based bryostatin analogs can inhibit CHIKV replication through a novel, yet still elusive, non-PKC dependent pathway.
KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
Rana
R
Abdelnabi
Stanford University, Departments of Chemistry and Chemical and Systems Biology, CA 94305, USA.
Daryl
D
Staveness
Stanford University, Departments of Chemistry and Chemical and Systems Biology, CA 94305, USA.
Katherine E
KE
Near
Stanford University, Departments of Chemistry and Chemical and Systems Biology, CA 94305, USA.
Paul A
PA
Wender
KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
Leen
L
Delang
KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium. Electronic address: Johan.Neyts@rega.kuleuven.be.
Johan
J
Neyts
KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
Pieter
P
Leyssen
D000107:Acetylation; D000818:Animals; D000998:Antiviral Agents / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054713:Bryostatins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002646:Chikungunya virus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D002522:Chlorocebus aethiops; D015195:Drug Design; D004357:Drug Synergism; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008745:Methylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D012672:Semliki forest virus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D012845:Sindbis Virus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D054713:Bryostatins; D002227:Carbazoles; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D014764:Viral Proteins; C081021:Go 6976; C543528:sotrastaurin; D011493:Protein Kinase C
Bryostatin; Chikungunya virus; Protein kinase C; Salicylate; Sotrastaurin
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