Question

Nucleotide metabolism and its Antiviral importance?

write about nucleotide metabolism and its Antiviral importance with reaction?

Answer 1

Human pyrimidine nucleotide biosynthesis has been targeted for the treatment of many diseases.Whereas most drugs that block pyrimidine nucleotide biosynthesis are targeted at cancer chemotherapy or immunosuppression, a deeper understanding of these metabolic pathways in humans could also be the foundation for the design of novel antiviral therapies. When viruses infect host cells, they up-regulate nucleotide biosynthetic flux [65]. Therefore, not only would inhibitors of nucleotide biosynthesis have the potential to neutralize a wide range of viruses, but their likelihood of eliciting drug-resistant mutants may also be lower than drugs targeted at viral proteins.

Although inhibitors of de novo pyrimidine nucleotide synthesis are known to exhibit broad-spectrum antiviral activity in vitro. they are ineffective in vivo due to efficient salvage of exogenous uridine. In this regard, The recent discovery that blocking the UCK isozyme, UCK2, sharply sensitizes cells toward DHODH inhibitors in the presence of a non-limiting uridine supply opens a new door for designing a combination antiviral agent comprised of a DHODH and a UCK2 inhibitor antiviral. Inhibition of both the de novo and the salvage pyrimidine synthesis could be particularly effective at limiting the fast proliferation of RNA viruses. In fact, a combination regimen containing PALA and dipyridamole has been tested in clinical trials for the treatment of cancer, albeit with limited efficacy. Weak activity could be due to inefficient inhibition of de novo pyrimidine synthesis by a CAD inhibitor as opposed to a DHODH inhibitor.

Since CMPK1 inhibition was also shown to sensitize cells to DHODH inhibitors, a similar outcome might also be achieved with a CMPK1 inhibitor. Indeed, given the location of CMPK1 at the convergence point of de novo biosynthesis and salvage, a sufficiently potent CMPK1 inhibitor could also be an effective form of monotherapy. However, unlike a DHODH/UCK2 combination agent, a CMPK1 inhibitor would also be expected to block the salvage of CMP and UMP derived from RNA degradation, and may therefore have a narrower therapeutic window.