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.
Our lab is captivated by the boundless potential of nanobodies, and we have developed powerful proteomic technologies to deconstruct the diverse array of serum-circulating nanobodies. By using this approach, we can uncover thousands of highly specific and multiepitope nanobodies, often with unprecedented affinity, that can be harnessed for drug development. For instance, we have recently generated a vast repertoire of broad-spectrum ultrapotent nanobodies against SARS-CoV-2 and other SARS-like viruses, which can be used to fight against the current pandemics and future outbreaks. By collaborating with structural biologists and modellers, we are investigating the structural basis of ultrahigh-affinity nanobody binding to disease targets.
Another emerging area of active research in our lab is the development of hybrid techniques, including the use of artificial intelligence, to facilitate protein design. This allows us to improve the efficiency and precision of our research, leading to new discoveries and innovations in the field.
Furthermore, we are constantly seeking new ways to identify novel targets for challenging diseases, with the ultimate goal of developing future pharmacological interventions, and making real-world impact.
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.