Shi Laboratory of Proteomics

and Protein Engineering

Center for Protein Engineering and Therapeutics
Department of Pharmacological Sciences
Icahn School of Medicine at Mount Sinai

Welcome to our laboratory!

We are a team of passionate scientists, committed to pushing the boundaries of biomedical sciences. Our aim is to develop proteomic techniques that will revolutionize the way we discover, create and engineer biomolecules with therapeutic potentials. Our research is not only about gaining an understanding of the fundamental principles, but also about making a tangible and meaningful impact on the world. We are thrilled to take on these challenges and eagerly anticipate the breakthroughs and innovations that we will accomplish together.

Research

Our research focuses on developing mass spectrometry-based proteomic techniques to study biology and facilitate drug discovery.

One significant aspect is the development of proteomic methods and software tools for the deconvolution of serum antibody repertoires, specifically Llama VHH antibodies- so called nanobodies. Nanobodies are small antibody fragments derived from camelid species, known for their excellent translational potential. Our lab has harnessed these nanobodies for therapeutic development by developing powerful proteomic techniques and software for high throughput nanobody drug discovery. We have discovered thousands of broad neutralizing nanobodies with often unprecedented potency against SARS-CoV-2 and other SARS-like viruses, offering potential solutions to combat current and future pandemics. We have also solved high-resolution structures of these antiviral nanobodies, providing insights into the mechanisms by which they inhibit viral infections. Additionally, Our team has shown the outstanding efficacy of engineered nanobodies for inhalation therapy, highlighting their potential as therapeutic agents for treating pulmonary infections.

Another area of active research in our lab involves the development of hybrid techniques that combine machine learning with high-throughput screening by proteomics. These approaches aim to facilitate protein engineering and design to improve “smart” drug development.

Publications

Integrative proteomics identifies thousands of distinct, multi-epitope, and high-affinity nanobodies

The antibody immune response is essential for the survival of mammals. However, we still lack a systematic understanding of the antibody repertoire. Here, we developed a proteomic strategy to survey, at an unprecedented scale, the landscape of antigen-engaged, circulating camelid heavy-chain antibodies, whose minimal binding fragments are called VHH antibodies or nanobodies. The sensitivity and robustness of this approach were validated with three antigens spanning orders of magnitude in immune responses; thousands of distinct, high-affinity nanobody families were reliably identified and quantified. Using high-throughput structural modeling, cross-linking mass spectrometry, mutagenesis, and deep learning, we mapped and analyzed the epitopes of >100,000 antigen-nanobody complexes. Our results revealed a surprising diversity of ultrahigh-affinity camelid nanobodies for specific antigen binding on various dominant epitope clusters. Nanobodies utilize both shape and charge complementarity to enable highly selective antigen binding. Interestingly, we found that nanobody-antigen binding can mimic conserved intracellular protein-protein interactions. A record of this paper's Transparent Peer Review process is included in the Supplemental information.