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Development of a simple, label-free screening technique capable of precisely and directly sensing interaction-in-solution over a size range from small molecules to large proteins such as antibodies could offer an important tool for researchers and pharmaceutical companies in the field of drug development. In this work, we present a thermostable Raman interaction profiling (TRIP) technique that facilitates low-concentration and low-dose screening of binding between protein and ligand in physiologically relevant conditions. TRIP was applied to eight protein–ligand systems, and produced reproducible high-resolution Raman measurements, which were analyzed by principal component analysis. TRIP was able to resolve time-depending binding between 2,4-dinitrophenol and transthyretin, and analyze biologically relevant SARS-CoV-2 spike-antibody interactions. Mixtures of the spike receptor–binding domain with neutralizing, nonbinding, or binding but nonneutralizing antibodies revealed distinct and reproducible Raman signals. TRIP holds promise for the future developments of high-throughput drug screening and real-time binding measurements between protein and drug. 

Abstract In a viral pandemic, a few important tests are required for successful containment of the virus and reduction in severity of the infection. Among those tests, a test for the neutralizing ability of an antibody is crucial for assessment of population immunity gained through vaccination, and to test therapeutic value of antibodies made to counter the infections. Here, we report a sensitive technique to detect the relative neutralizing strength of various antibodies against the SARS-CoV-2 virus. We used bright, photostable, background-free, fluorescent upconversion nanoparticles conjugated with SARS-CoV-2 receptor binding domain as a phantom virion. A glass bottom plate coated with angiotensin-converting enzyme 2 (ACE-2) protein imitates the target cells. When no neutralizing IgG antibody was present in the sample, the particles would bind to the ACE-2 with high affinity. In contrast, a neutralizing antibody can prevent particle attachment to the ACE-2-coated substrate. A prototype system consisting of a custom-made confocal microscope was used to quantify particle attachment to the substrate. The sensitivity of this assay can reach 4.0 ng/ml and the dynamic range is from 1.0 ng/ml to 3.2  $$\upmu$$ μ g/ml. This is to be compared to 19 ng/ml sensitivity of commercially available kits. 

Abstract Dr. Deborah Birx, the White House Coronavirus Task Force coordinator, told NBC News on “Meet the Press” that “[T]he U.S. needs a ‘breakthrough’ in coronavirus testing to help screen Americans and get a more accurate picture of the virus’ spread.” We have been involved with biopathogen detection since the 2001 anthrax attacks and were the first to detect anthrax in real-time. A variation on the laser spectroscopic techniques we developed for the rapid detection of anthrax can be applied to detect the Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2 virus). In addition to detecting a single virus, this technique allows us to read its surface protein structure. In particular, we have been conducting research based on a variety of quantum optical approaches aimed at improving our ability to detect Corona Virus Disease-2019 (COVID-19) viral infection. Indeed, the detection of a small concentration of antibodies, after an infection has passed, is a challenging problem. Likewise, the early detection of disease, even before a detectible antibody population has been established, is very important. Our team is researching both aspects of this problem. The paper is written to stimulate the interest of both physical and biological scientists in this important problem. It is thus written as a combination of tutorial (review) and future work (preview). We join Prof. Federico Capasso and Editor Dennis Couwenberg in expressing our appreciation to all those working so heroically on all aspects of the COVID-19 problem. And we thank Drs. Capasso and Couwenberg for their invitation to write this paper.