Targeting Neuroinvasive Infections associated to Flaviviruses with Nucleoside Analogues

"Viral illnesses pose a serious threat to our societies, as demonstrated by the COVID19 pandemic and the AIDS global problem. In addition to containment and prevention strategies, therapeutic and prophylactic initiatives have produced notable achievements, such as control of the HIV and Hepatitis C virus. Despite questions about their limitations, nucleoside/tide analogues still represent one of the most effective classes of antiviral drugs to date. Our therapeutic and preventive defensive tactics against new viruses have major weaknesses, as exemplified by the COVID-19 crisis. Early in 2020, the alarming discovery that SARS-CoV-2 could exhibit neurotropism presented an additional challenge to the implementation of an antiviral arsenal. It is now recognized that the virus neurotropism is responsible for the significant burden of long-term COVID cases, and that this burden may be reduced in the future by starting appropriate therapeutic treatments as soon as feasible, either before or during (primo)infection. Unfortunately, because of the unique construction of the blood-brain barrier (BBB) and the chemical structure/properties unique to each NA, only a few enter the central nervous system. Acyclovir and zidovudine are two examples of NAs that have been shown to do so; nonetheless, there is a significant information gap for the majority of NAs, especially with regard to new RNA viruses. It has long been a challenge in the antiviral research field to deliver NAs to the appropriate tissue. In the case of hepatic viruses, this has been remarkably and successfully (but solely) accomplished through the use of ProTide prodrugs. The potency of each NA, or matching prodrug, precedes specific integration into viral RNA by the viral polymerase and is dependent on the prodrug's cell entrance and activation by host enzymes, up to the active 5'-triphosphate (NA-TP) form. Viruses with a systemic distribution are not reached by antivirals equally in every tissue because activation is cell-type dependent. This is especially relevant to the CNS, which is heavily shielded by the so-called BBB. Consequently, we intend to develop: i) a type of prodrug promoting uptake and activation of NAs; and ii) a model viral system and setup that will enable accurate drug-design follow-up. The aim of the NeuroFlaviNA project is to provide a complete pipeline to this endeavor directed towards pathogenic neurotropic Orthoflaviviruses of significant clinical impact. Arboviruses are one of the main types of emerging viruses of concern for human and animal health. Among them, Orthoflaviviruses are spreading throughout France and Europe and are becoming increasingly prevalent. For instance, the consumption of tainted dairy products in France resulted in an epidemic of the tick encephalitis virus, which has since expanded its geographic range. Additionally, the West-Nile virus was discovered for the first time at latitudes higher than those previously reported and on the French Atlantic coast. These two Orthoflaviviruses possess a similar tropism that can result in potentially lethal neuroinvasion, as do Japanese encephalitis and Usutu viruses. The overall objective of the NeuroFlaviNA project is to discover novel molecules (either nucleoside analogues, their prodrugs or conjugates) allowing CNS delivery of ribonucleoside-based antivirals targeting emerging or re-emerging neurotropic Orthoflaviviruses. In this respect, 3 interconnected work packages (WP1-3), including 8 tasks, through a complementary consortium of 7 partners, have been proposed over a 36-month period."