Intrinsic disorder in flaviviral capsid proteins and its role in pathogenesis.

A high level of disorder in many viral proteins is a direct consequence of their small genomes, which makes interaction with multiple binding partners a necessity for infection and pathogenicity. A segment of the flaviviral capsid protein (C), also known as the molecular recognition feature (MoRF), undergoes a disorder-toorder transition upon binding to several protein partners. To understand their role in pathogenesis, MoRFs were identified and their occurrence across different flaviviral capsids were studied. Despite lack of sequence similarities, docking studies of Cs with the host proteins indicate conserved interactions involving MoRFs across members of phylogenetic subclades. Additionally, it was observed from the protein-protein networks that some MoRFs preferentially bind proteins that are involved in specialized functions such as ribosome biogenesis. The findings point to the importance of MoRFs in the flaviviral life cycle, with important consequences for disease progression and suppression of the host immune system. Potentially, they might have impacted the way flaviviruses evolved to infect varied hosts using multiple vectors.

3', 4'-dihydroxyflavone ameliorates paclitaxel model of peripheral neuropathy in mice by modulating KATP channel, adenosine (A3) and GABAA (α2 subunit) receptors.

Paclitaxel is a widely used cancer chemotherapeutic agent for many solid tumors; but peripheral neuropathy is a major limitation for its clinical use. Studies have demonstrated the usefulness of flavone derivatives in chemotherapy induced peripheral neuropathy. The present study evaluates the anti-neuropathic effect of 3', 4'-dihydroxyflavone on paclitaxel-induced peripheral neuropathy and the underlying mechanisms. Paclitaxel was administered to mice in a single dose of 10 mg/kg, i.p.The neuropathic behavioural parameters such as mechanical allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later. The test compound 3', 4'-dihydroxyflavone (50,100 or 200 mg/kg,s.c) was administered 30 min prior to the assessment of behavioral parameters. The possible mechanisms involving KATP channels, adenosine and GABAA receptors were explored by employing suitable interacting drugs. Molecular docking studies to predict the binding interactions of 3', 4'-dihydroxyflavone at the above targets were also carried out. The test compound 3', 4'-dihydroxyflavoneexhibited a significant reduction in paw withdrawal response score in both mechanical and cold allodynia and also increased the tail flick response time in thermal hyperalgesia due to paclitaxel-induced neuropathy. The anti-neuropathic effect of 3', 4'-dihydroxyflavonewas significantly reversed by pre-treatment with glibenclamide, caffeine or bicuculline revealing the involvement of KATP channels, adenosine and GABAA receptors respectively. Furthermore, the molecular docking studies indicated a favourable binding affinity and good H-bond interaction of 3', 4'-dihydroxyflavone at these targets. The findings of the present study suggests that, 3', 4'-dihydroxyflavone has anti-neuropathic effect against paclitaxel-induced peripheral neuropathy through mechanisms that involve KATP channels, adenosine (A3) and GABAA (α2 subunit) receptors.

Anti-neuropathic effect of 7,3'-dihydroxyflavone in paclitaxel induced peripheral neuropathy in mice involving GABAA, KATP channel and adenosine receptors.

Peripheral neuropathy induced by chemotherapeutic agents is the most common dose-limiting adverse effect observed in patients during and after treatment of malignancies. Many flavones have been reported to ameliorate neuropathy of different origin in experimental animals and their possible mode of action explored. The present study aims to investigate 7,3'-dihydroxyflavone for its anti-neuropathic effect against paclitaxel induced peripheral neuropathy in mice by employing behavioural tests such as mechanical allodynia, cold allodynia and thermal hyperalgesia. The possible involvement of GABAA, KATP channels and adenosine receptors in the anti-neuropathic effect of 7,3'-dihydroxyflavone was also studied by employing suitable interacting drugs. Treatment with 7,3'-dihydroxyflavone (50, 100 or 200 mg/kg, s.c) significantly and dose-dependently reduced the paw withdrawal response score in both mechanical and cold allodynia and also increased the tail flick response time in thermal hyperalgesia due to paclitaxel-induced neuropathy. Pre-treatment with glibenclamide (10 mg/kg, i.p), caffeine (50 mg/kg, i.p) or bicuculline (2 mg/kg, i.p) significantly reversed the anti-neuropathic effect of 7,3'-dihydroxyflavone in behavioral tests. In conclusion, the present investigation identified 7,3'-dihydroxyflavone as a potential candidate with anti-neuropathic effect against paclitaxel induced peripheral neuropathy involving KATP channels, adenosine and GABAA receptors.