We have developed a new technique that allows commercially-sourced silicon field-effect transistors (FETs) operating as readout elements for biosensor to achieve a 3-fold improvement in pH resolution over conventional ion-sensitive field-effect transistors (ISFETs). This was achieved by operating the devices under closed-loop control, actively nulling any input to the gate terminal from charge fluctuations at a sensing surface. The response of the sensor was therefore, the output signal of the controller. The improved pH resolution was realized while the devices were operated in a remote configuration with the pH sensing surface off-chip and connected electrically to FET gate terminal. We leveraged the improved FET performance to measure the activity of a pathological form of the kinase Cdk5, an enzyme implicated in Alzheimer’s disease, and demonstrated the effectiveness of a custom polypeptide, p5, as a therapeutic agent in restoring the function of Cdk5. We expect that the simple modifications to commercially-sourced FETs demonstrated here will lower the barrier to widespread adoption of these devices for drug discovery and clinical diagnostics. This new technology is linked to our previous disclosures in this area (Docket #16-019/US 2017/0261465; Docket #19-003).