Central dogma of biology DNAàRNAàProtein is successfully exploited to understand fundamental biology and to apply principles of evolution to discover lifesaving therapeutics. Many advances are fueled by technological breakthroughs in DNA sequencing, which for the last 40 years developed faster than the Moore’s law. Traditional chemistry and majority of the biology falls outside the Central Dogma, and, thus, cannot rely on DNA sequencing directly.  For example, studying the role of glycans and other post-translational modifications (PTM) in vivo is the fundamental lack of one-to-one correspondence between sequence of DNA and structures of carbohydrates and PTM. Molecular discovery, reaction and catalyst discovery can be dramatically accelerated by shifting from traditional discovery approaches to DNA-encoded evolutionary approaches. As a contribution to this field, our group introduced platform technologies termed Liquid Glycan Array (LiGA) [1-4], Liquid Lectin Array (LiLA) [5], broad class of DNA-encoded “Liquid Molecular Arrays” as well as DNA-encoded chemical PTM (DE-cPTM) in genetically-encoded libraries [6]. This talk will present development and application of LiGA/LiLA/LiMA technologies and DE-cPTM technologies.

LiGA, produced by chemoenzymatic ligation of carbohydrates to bacteriophage, introduce one-to-one correspondence between DNA sequence and glycan displayed on phage. It enables unsupervised profiling of interactions of glycans with receptors on the surface of cells ex vivo and in vivo. Complimentary LiLA technology can detect specific glycoisoforms on live cells. Injection of the liquid arrays into mice identifies interactions necessary for homing to specific organs. I will also review a broader LiMA technology and DE-cPTM specifically for development of therapeutic leads in radiopharmaceuticals. These technologies made it possible to study the fundamental role of chirality in molecular recognition and we will present out initial work on cross-chiral recognition of glycans and proteins, components of innate immune system [7].

1. Sojitra et al., “Genetically encoded multivalent liquid glycan array displayed on M13 bacteriophage”, Nat. Chem. Biol. 2021, 17, 806
2. Lin et al., “Chemoenzymatic Synthesis of Genetically-Encoded Multivalent Liquid N-glycan Arrays” Nat. Comm., 2023, 14, 5237
3. Sojitra et al., “Measuring carbohydrate recognition profile of lectins on live cells using liquid glycan array (LiGA)”, Nat. Protocols 2024, doi.org/10.1038/s41596-024-01070-3
4. Schmidt et al., “Siglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket” Nat. Comm. 2023, 14, 2327
5. GM Lima, et al., “The liquid lectin array detects compositional glycocalyx differences using multivalent DNA-encoded lectins on phage” Cell Chem. Biol. 2024
6. Ekanayake et al., “Genetically Encoded Fragment-Based Discovery from Phage-Displayed Macrocyclic Libraries with Genetically Encoded Unnatural Pharmacophores” JACS 2021, 143, 14, 5497
7. Derda et al., “Remember The Glycans: Consideration of Glycans in Evaluating the Threat of Mirror-Image Life Forms” Science 2025, eLetter