Pharmacogenomics
Long-read sequencing offers path to more accurate drug metabolism profiles
In the complex drug discovery process, one of the looming questions for any new compound is how it will be metabolised in a human body. While there are several methods for evaluating this, one of the most common involves CYP2D6, the enzyme encoded by the cytochrome P450-2D6 gene. This enzyme is involved in metabolising a quarter of all commonly used medications, making it an important target for ADME and pharmacogenomics studies. It is known to activate some drugs and to play a role in the deactivation or excretion of others.
By Dr Jenny Ekholm T
he CYP2D6 gene harbours many variants that contribute to the differences in how people metabolise everything from antipsychotic therapies to painkillers. From a pharmacology perspective, it is critical to under- stand the function of this gene in order to develop the best possible compounds, determine optimal dosing protocols, and target drugs to the right patient population. However, elucidating CYP2D6 function through variant detection has been a remarkably difficult task. The gene is highly polymorphic, with more than 150 different alleles classified for it – a num- ber that is expected to keep growing. CYP2D6 is known for complex structural variations, such as rearrangements, duplications and deletions. To make matters worse, it has a nearby pseudogene with incredibly high sequence identity; efforts to
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query CYP2D6 are frequently confounded by mis- leading results from this pseudogene. Interrogating this important gene is typically done through genotyping or sequencing. FDA- approved molecular diagnostic platforms scan the gene, looking for only the most common alleles. These platforms cannot identify novel alleles, nor can they distinguish clinically meaningful variants reflective of a less common allele. In drug discov- ery research, scientists often use TaqMan assays or Luminex for genotyping, while some use Sanger sequencing or short-read sequencing to characterise CYP2D6. Unfortunately, these sequencing technologies lack the resolution need- ed to provide a clear and accurate picture of the gene and its pseudogene. Recently, long-read sequencing has become an alternative approach for resolving this region.
Drug Discovery World Summer 2017
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