Drug targeting, design, and clinical trials

Initially antiviral compounds were discovered in an empirical fashion; chemical synthe- sis of a wide range of compounds followed by testing of antiviral activity in cell culture. The increasing knowledge of the molecular basis of virus replication processes, the availability of complete nucleotide sequences of virus genomes and three-dimensional pro- tein structure information means that compounds can now be more precisely designed to interact with specific targets and active sites on essential viral proteins. In practice the most useful targets are viral enzymes that have properties or activities different to those of the counterpart enzymes in host cells (e.g. thymidine kinase, DNA polymerase, reverse transcriptase, and protease). Through gene  cloning, it is possible to  express, purify,  crystallize, and  examine the  three-dimensional structure of individual virus pro- teins and  use  this  information to determine molecular structures predicted to interact with  particular sites  in the  viral protein. In addition, features such as low toxicity and production costs are highly important, given the enormous cost of developing a potential candidate to clinical application and market. The majority of costs are split between the scientific research necessary to identify and test the compounds, and clinical trials that establish its effectiveness and safety in vivo.  Clinical trials must pass, in order, through several tightly regulated phases.

Phase I involves administering the drug candidate to healthy human volunteers where studies on the pharmacokinetics, pharmacology, and metabolism of the compound are monitored.

Phase II the compound is administered to disease patients, with a view to assessing data similar to those of Phase I, as the metabolism may be different compared with a healthy individual. Usually in excess of 100 patients are needed for these trials to give reliable data.

Phase III the drug is usually tested for its clinical efficacy by comparing with placebos or existing drugs. The main aim is to determine the benefit/risk ratio for the therapeutic course, and this phase requires 100–1000 patients. In many, but not all Phase III trials, the drug and placebo are administered randomly, such that neither the test subjects nor the trial administrators know which individual has received which treatment. This is known as a double-blind trial and is important to safeguard the unbiased observation, recording, and interpretation of clinical outcomes. In certain circumstances Phase III trials are conducted without placebos (i.e. all patients receive the drug), as withholding of the drug and its potential therapeutic value would be unethical.

Phase IV studies are  usually conducted  following marketing approval and  increased experience of treating patients, providing more information on safety and  efficacy.

Sadly  most potential antiviral compounds, although good  inhibitors of virus  protein activity  in biochemical tests,  or even  of viral replication in cell culture, fail to pass  suc- cessfully through all of the phases of clinical studies and  are ultimately rejected.