FLAVITHERAPEUTICS

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FLAVITHERAPEUTICS “Research, selection and mechanism of action of potential therapeutic agents against Flaviviridae(Hepatitis C virus, Dengue virus, West Nile virus)”Type of Project: Integrated Project

Duration: January 2002 – January 2005

Total EU grant: € 1.901.408,00

Section grant: € 321.468,00

Role: Coordinator

Abstract

Six internationally recognized research laboratories proposed to work in close cooperation within the European Union on a biomedical program entitled “Research, selection and mechanism of action of potential therapeutic agents against Flaviviridae”.
The Flaviviridae family of viruses includes the hepatitis C virus responsible for infectious hepatitis and hepatocellular carcinoma in over 170 million persons worldwide, as well as dengue (DENV) and West Nile (WNV) viruses that pose an ever growing deadly threat to the unprotected human population in Europe and elsewhere. One potential vulnerability of such pathogenic RNA viruses is their mistaken recognition of certain modified “building blocks” in place of the four natural ribofuranonucleotides (ATP, GTP, CTP and UTP) used for the biosynthesis and replication of their genetic material. It was proposed that specifically “altered” or engineered ribonucleoside analogues will act as lethal surrogates when the viruses attempt to propagate. The organic chemistry objective of this work, included the synthesis of these novel ribonucleoside analogues, including the D and L enantiomeric forms, modified on the purine or pyrimidine bases, or on the sugar moieties. These synthetic compounds were similar in shape to their natural counterparts, and should be accepted by the enzymes needed to activate them to their phosphate derivatives but unrecognised by, and non-cytotoxic to, normal cellular functions.
The ultimate goal of the consortium was to design new nucleoside analogues, suitable for further preclinical and clinical development, that interfere specifically with the replication processes of 3 viruses of the Flaviviridae family [Hepatitis C virus (HCV), dengue virus (DENV) and West Nile virus (WNV)]. These are known for their major impact in human pathology in Europe, European outer-most regions and inter tropical low-income countries.
From a research point of view, the objective was to take advantage of major homologies and slight differences among these three viruses in the replication enzyme apparatus. This led to the design of specific therapeutic substances for the class of Flaviviridae as a whole.