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.