Functional genomics and cardiovascular drug discovery.

Abstract

The history of cardiovascular drug discovery is filled with delightful stories of serendipity. Had William Withering not first advanced his expertise in botany to court Helena Cook, a young woman who enjoyed painting flowers and later became his wife, he may not have been able to identify foxglove as a therapy for heart failure.1 Similarly, warfarin owes its discovery not to a search for therapeutic anticoagulants, but to studies of a hemorrhagic disease of cattle that devastated the American northern prairie farming community in the 1920s.2 More recently, cardiovascular drugs have arisen less from chance and more from logical scientific approaches. The development of captopril, for example, depended on an understanding of the active site of the angiotensin-converting enzyme and logical chemical modifications of active site antagonists.3 However, advances in genomic technology over the past several years have transformed drug discovery. This article will provide an overview of one new approach to drug discovery that is often called Functional Genomics. Although the progress of the Human Genome Project and privately-funded genome databases enabled the functional genomics approach, other powerful uses of the genome in drug discovery will be not be discussed in detail here. For example, single-base genomic differences between individuals called single nucleotide polymorphisms are common in candidate genes for cardiovascular diseases4 and can be used to identify genes associated with disease susceptibility in populations. Genes associated with disease susceptibility are obvious potential targets for novel therapies, although many of these genes may not be suitable targets for drugs. Single nucleotide polymorphisms may also be used to identify patients who may respond to specific therapies. Clinicians are aware that some patients benefit from a given drug while others do not; the science of pharmacogenetics aims to identify the genetic basis for this variation.5 Thus, …