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Rapid, quantitative therapeutic screening for Alzheimer's enzymes enabled by optimal signal transduction with transistors

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Abstract

We show that commercially sourced n-channel silicon field-effect transistors (nFETs) operating above their threshold voltage with closed loop feedback to maintain a constant channel current allow a pH readout resolution of (7.2 ± 0.3) × 10−3 at a bandwidth of 10 Hz, or ≈3-fold better than the open loop operation commonly employed by integrated ion-sensitive field-effect transistors (ISFETs). We leveraged the improved nFET performance to measure the change in solution pH arising from the activity of a pathological form of the kinase Cdk5, an enzyme implicated in Alzheimer's disease, and showed quantitative agreement with previous measurements. The improved pH resolution was realized while the devices were operated in a remote sensing configuration with the pH sensing element off-chip and connected electrically to the FET gate terminal. We compared these results with those measured by using a custom-built dual-gate 2D field-effect transistor (dg2DFET) fabricated with 2D semi-conducting MoS2 channels and a signal amplification of 8. Under identical solution conditions the nFET performance approached the dg2DFETs pH resolution of (3.9 ± 0.7) × 10−3. Finally, using the nFETs, we demonstrated the effectiveness of a custom polypeptide, p5, as a therapeutic agent in restoring the function of Cdk5. We expect that the straight-forward modifications to commercially sourced nFETs demonstrated here will lower the barrier to widespread adoption of these remote-gate devices and enable sensitive bioanalytical measurements for high throughput screening in drug discovery and precision medicine applications.

Graphical abstract: Rapid, quantitative therapeutic screening for Alzheimer's enzymes enabled by optimal signal transduction with transistors

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Supplementary files

Article information


Submitted
13 Sep 2019
Accepted
04 Mar 2020
First published
04 Mar 2020

Analyst, 2020, Advance Article
Article type
Paper

Rapid, quantitative therapeutic screening for Alzheimer's enzymes enabled by optimal signal transduction with transistors

S. T. Le, M. A. Morris, A. Cardone, N. B. Guros, J. B. Klauda, B. A. Sperling, C. A. Richter, H. C. Pant and A. Balijepalli, Analyst, 2020, Advance Article , DOI: 10.1039/C9AN01804B

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