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.

Marine natural products

“…Furthermore only amanthaspiramindes A, C and E containing a pyrrolidine and 8R conguration of the N-acyl hemiaminal moiety showed antiproliferative activity. A series of simplied bryostatin analogues 671 and salicylate-derived bryostatin analogues 672 were prepared and exhibited very potent anti-Chikungunya virus activity. 671,672…”

Unlocking the Drug Potential of the Bryostatin Family: Recent Advances in Product Synthesis and Biomedical Applications

“…To investigate the effect of the A/B‐ring system on the antiviral activity of the salicylate‐derived analogues, Wender et al. designed and synthesized eighteen new compounds by diversifying at the C7‐, C8‐, C9‐, and C13‐position of the scaffold (Figure ) . To evaluate their anti‐CHIKV activity, EC 50 and CC 50 values were compared.…”

“…[60] To investigate the effect of the A/Bring system on the antiviral activity of the salicylate-derived analogues,W ender et al designed and synthesized eighteen new compounds by diversifying at the C7-, C8-, C9-, and C13-posi-tion of the scaffold ( Figure 5). [61] To evaluatet heir anti-CHIKV activity,E C 50 and CC 50 values were compared. EC 50 and CC 50 are measureso ft he cell-protective anda nalogue-induced adverse effects on malignant cells, respectively (EC 50 = concentration of compound that reduces the CHIKV-induced cytopathic effect by 50 %, CC 50 = concentration at whichcell viability is 50 %relative to untreated cells as ar esult of treatment with compound alone).…”

Current Strategies for Inhibition of Chikungunya Infection

“…Recently, bryostatin analogues were reported to exhibit high potency and low toxicity against CHIKV based on their ability to modulate PKC [ 167 ]. Interestingly, bryostatin 1, which is a potent pan-PKC modulator, was inactive against CHIKV in the same assay.…”