Proceedings of the National Academy of Sciences · 2005 · 534 citations · 22 references
EngineeringBioengineeringPharmacologyBiosensorsDrug DiscoveryNanotechnologyLigand BindingMicrofluidic BiosensorsNanosensorsNanowiresProtein-ligand BindingProtein-ligand InteractionsLabel-free DetectionNanowire BiosensorsNanowire DevicesNanowire Field-effect TransistorsNanowire SensorsSilicon NanowiresSmall Molecule Tyrosine Kinase InhibitorsTyrosine Kinase Inhibition
Miniaturized devices that rapidly and directly analyze small‑molecule binding to proteins are crucial for drug discovery and screening. Silicon nanowire field‑effect transistors were functionalized with Abl kinase and, within microfluidic channels, monitored conductance changes to quantify ATP binding and its inhibition by STI‑571 and four other small molecules. The devices achieved highly sensitive, label‑free detection of ATP binding inhibition, distinguishing inhibitor affinities and demonstrating potential as a drug‑discovery platform.
Development of miniaturized devices that enable rapid and direct analysis of the specific binding of small molecules to proteins could be of substantial importance to the discovery of and screening for new drug molecules. Here, we report highly sensitive and label-free direct electrical detection of small-molecule inhibitors of ATP binding to Abl by using silicon nanowire field-effect transistor devices. Abl, which is a protein tyrosine kinase whose constitutive activity is responsible for chronic myelogenous leukemia, was covalently linked to the surfaces of silicon nanowires within microfluidic channels to create active electrical devices. Concentration-dependent binding of ATP and concentration-dependent inhibition of ATP binding by the competitive small-molecule antagonist STI-571 (Gleevec) were assessed by monitoring the nanowire conductance. In addition, concentration-dependent inhibition of ATP binding was examined for four additional small molecules, including reported and previously unreported inhibitors. These studies demonstrate that the silicon nanowire devices can readily and rapidly distinguish the affinities of distinct small-molecule inhibitors and, thus, could serve as a technology platform for drug discovery.
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Nanowire Nanosensors for Highly Sensitive and Selective Detection of Biological and Chemical Species
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