Nucleosides

A brief history:

For over fifty years nucleoside analogs have been used to treat a variety of viral diseases and cancers.  Idoxuridine, the first antiviral drug, was approved in 1963 and is still used to treat herpes simplex keratitis.  Six years later, Ara-C received FDA approval and is currently used to treat acute myeloid leukemia and non-Hodgkin lymphoma.  Subsequently, gemcitabine was developed to treat non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer, as was 5-fluorouracil for treating anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers.

The discovery of acyclovir as a safe and efficacious treatment for Herpes infections resulted in the awarding of the 1988 Nobel Prize in Physiology or Medicine to Gertrude Elion and George Hitchings.  In 1987 the approval of zidovudine marked the beginning of two decades of nucleoside therapeutic development that led to the approval of, inter alia, epivir, emtricitabine, tenofovir and abacavir and ultimately transformed AIDS from a death sentence to a manageable chronic infection.  Similarly, lamivudine became the first of many nucleoside analogs (e.g., entecavir, adefovir, tenofovir and telbivudine) that could be used to control hepatitis B infections.  Most recently, the FDA approved sofosbuvir in combination with ribavirin for oral dual therapy of hepatitis C infections (genotypes 2 and 3).  As a consequence of these and other successes, nucleoside therapeutics collectively must be considered to be one of the most robust and versatile classes of drugs available today.

FDA Approved Nucleosides

This notwithstanding, there are still many important unmet medical needs that could potentially be handled by nucleosides.  The Liotta Research Group is continuing our work on developing new antiretroviral agents for HIV that target privileged compartments not readily accessed by the currently available therapies

An Introduction:

Viral disease represents a major burden to human civilization.  Viruses are often difficult to eradicate due to their ease of transmissibility, as well as their ability to utilize host biochemical pathways to replicate.  Therefore, targeting viral components often presents the difficult challenge of reducing viral load in a host without damaging it.  One of the most successful methods to fight viral disease is the use of nucleoside analogues to inhibit a viral polymerase, thereby interfering with viral genome replication.

Nucleosides and nucleotides are molecules that are the building blocks of DNA and RNA.  Figure 1 below shows the various locations of DNA and RNA in a human cell and in a virus.

Figure 1.

Figure 2 zooms in on viral nucleic acid, illustrating that the material is composed of a linear sequence of nucleotides: the A’S, T’s G’s and C’s. The chemical structures of these components are shown in Figure 3.

Figure 2.

Figure 3.

A nucleotide is one unit of these nucleic acid polymers.  One of the key steps in viral propagation is the copying of the viral genome, and inhibition of this process reduces the amount of virus in the host.

 

Figure 4.

 

DNA and RNA polymerases (Red enzyme in Figure 4) catalyze the synthesis of DNA and RNA polymers from nucleotide precursors. Synthetic nucleotide triphosphates and nucleosides (unphosphorylated nucleotides) can bind to the enzyme and inhibit polymerization when they are linked to the growing chain by either having no place for attachment for new nucleotides or by blocking new nucleotides from entering to the polymerase pocket.

 

Current Work:

Our laboratory is continuing to develop new antiretroviral agents for HIV. These molecules are designed to target privileged tissue compartments not readily accessed by the currently available therapies.  Additionally, in collaboration with Drug Innovation Ventures at Emory (DRIVE) and the Emory Institute for Drug Development (EIDD), we are developing a variety of nucleoside analogs that are inhibitors of the RNA-dependent RNA polymerases (RdRps) of many single stranded RNA viruses.  Since there is structural conservation in the active sites of these RdRps, we have been able to quickly identify specific replication inhibitors of many of these viruses, including Venezuelan Equine Encephalitis virus (VEEV), Western Equine Encephalitis virus (WEEV), Chikungunya virus (CHIK), Hepatitis C virus (HCV) and Respiratory Syncytial virus (RSV). These viruses represent a substantial disease burden, and the Liotta group is working to generate therapeutic leads for these diseases, most of which lack effective and safe treatments or vaccines.

Our approach to antivirals is two-fold: the lab synthesizes new sugar and nucleobase cores for the construction of nucleoside antivirals and develops new prodrugs to deliver the active molecule selectively. With new sugar and nucleobase cores, we develop a structure-activity relationship (SAR) using organic synthesis and computational structural biology to find drug leads. We also collaborate with the drug metabolism / pharmacokinetics group (DMPK) in the EIDD to design and test new methods to deliver the active compound in our prodrug development program.