ABSTRACT
Since its onset in December 2019, severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, has caused over 6.5 million deaths worldwide as of October 2022. Attempts to curb viral transmission rely heavily on reliable testing to detect infections since a large number of transmissions are carried through asymptomatic individuals. Many available detection methods fall short in terms of reliability or point-of-care applicability. Here, we report an electrochemical approach targeting a viral proteolytic enzyme, 3CLpro, as a marker of active infection. We detect proteolytic activity directly from untreated saliva within one minute of sample incubation using a reduction-oxidation pH indicator. Importantly, clinical tests of saliva samples from 50 subjects show accurate detection of SARS-CoV-2, with high sensitivity and specificity, validated by PCR testing. These, coupled with our platform's ultrafast detection, simplicity, low cost and point-of-care compatibility, make it a promising method for the real-world SARS-CoV-2 mass-screening.