Limitations of the recognition elements in terms of synthesis, cost, availability, and
stability have impaired the translation of biosensors into practical use. Inspired by
nature to mimic the molecular recognition of the anti-SARS-CoV-2 S protein antibody
(Ab
S
) by the S protein binding site, we synthesized the peptide sequence of
Asn-Asn-Ala-Thr-Asn-COOH (abbreviated as PEP2003) to create COVID-19 screening
label-free (LF) biosensors based on a carbon electrode, gold nanoparticles (AuNPs), and
electrochemical impedance spectroscopy. The PEP2003 is easily obtained by chemical
synthesis, and it can be adsorbed on electrodes while maintaining its ability for
Ab
S
recognition, further leading to a sensitivity 3.4-fold higher than the
full-length S protein, which is in agreement with the increase in the target-to-receptor
size ratio. Peptide-loaded LF devices based on noncovalent immobilization were developed
by affording fast and simple analyses, along with a modular functionalization. From
studies by molecular docking, the peptide–Ab
S
binding was found to be
driven by hydrogen bonds and hydrophobic interactions. Moreover, the peptide is not
amenable to denaturation, thus addressing the trade-off between scalability, cost, and
robustness. The biosensor preserves 95.1% of the initial signal for 20 days when stored
dry at 4 °C. With the aid of two simple equations fitted by machine learning (ML),
the method was able to make the COVID-19 screening of 39 biological samples into healthy
and infected groups with 100.0% accuracy. By taking advantage of peptide-related merits
combined with advances in surface chemistry and ML-aided accuracy, this platform is
promising to bring COVID-19 biosensors into mainstream use toward straightforward, fast,
and accurate analyses at the point of care, with social and economic impacts being
achieved.