Fast proliferating cells, like tumor cells, or virally infected cells are highly dependent on de novo nucleotide synthesis. An inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) downregulates de novo pyrimidine nucleotide synthesis and thus limits cell growth and proliferation of fast proliferating cells. Hence, DHODH inhibitors could be excellent therapeutic in fields such as viral infections, immunosuppression or cancer treatment. Still, DHODH inhibitors have not yet been employed due to several shortcomings, e.g. minor inhibitory effect, unacceptable side-effects, toxicity or inconsistent pharmacokinetics.
A research group at a German university has developed novel DHODH inhibitors, which overcome these limitations and show a broad antiviral activity. This is achieved by suppressing the de novo synthesis of uridine monophosphate (UMP) based pyrimidine nucleotides, leading to limitations in cell growth and proliferation, especially for fast proliferation cells including tumor cells or virally infected cells, whereas the host cell’s demand for nucleotides is covered by the salvage pathway for resting cells.
The new DHODH inhibitors can be obtained in multi-gram scale via short synthetic routes. They show high antiviral activity down to the low nanomolar range in simian, mouse, hamster and human cell lines against several RNA virus families including bunya, flavi, hemorrhagic fever (e.g. Ebola) and toga with high selectivity. The new compounds are optimized regarding their metabolic stability and with respect to absorption, distribution, metabolism, and excretion properties (ADME) for in vivo testing.
The patented technology is offered for license agreements or transfer of rights, in case an industrial partner intends further in-house development of the technology and its commercialization.
The university involved is also open to discuss a research cooperation with industrial partners in order to further develop the technology together and reach a higher TRL. Agreements on research cooperation would usually include an option for the industrial partner to purchase the patent or obtain a license at later stage.