Targeting cellular and viral enzymes involved in hemorrhagic fever virus replication using new small molecule broad spectrum inhibitors

Project D01 addresses two approaches to design broad-spectrum antivirals against emerging infections. This chemistry-driven project involves two distinct targets: first, we aim to develop nucleotide-based inhibitors against viral RNA-polymerases and second, we will design small molecule inhibitors against a host cell enzyme essential for the de-novo synthesis of pyrimidine nucleotides.

Nucleoside analogues have been used as antivirals in the past. To be antivirally active, such compounds have to be converted into their triphosphate form which is the ultimate metabolite blocking the viral polymerase and thus preventing RNA replication. In contrast to previous drug development, we will develop polymerase inhibitors based on nucleoside triphosphates by using for example cryo-EM microscopy. Potent inhibitors will be chemically converted into lipophilic pronucleotides to enable membrane-permeability for in-vitro as well as in-vivo applications.

Large amounts of natural nucleotides are needed in case of a viral infection. Blocking DHODH by small synthetic molecules should result in a lack of pyrimidines in the nucleotide pool. The advantage of inhibiting essential cellular enzymes is the low risk of resistance development.

In summary, this project aims to block two essential enzymes either with individual chemicals or as a new combinational approach applicable to tackle “Disease X” in the future.