Aptamer-based LYTACs to screen for critical determinants of lysosomal degradation

$1,388R01FY2021GMNIH

Stanford University, Stanford CA

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Abstract

PROJECT ABSTRACT Extracellular and transmembrane proteins are central pathological components in cancer, aging-related disorders, and autoimmune disease. These proteins can be degraded using lysosome targeting chimeras (LYTACs), antibodies conjugated to polymeric chemical moieties engaging the cation-independent mannose-6- phosphate receptor (CI-M6PR). As these molecules require careful chemical synthesis, we will produce alternate LYTACs in high throughput using aptamers targeting CI-M6PR linked to nanobodies via enzymatic autoconjugation. This method will help elucidate optimal LYTAC binding affinities to CI-M6PR. We will further use enzymatic autoconjugation to produce aptamer-LYTACs within bacterial cells in a genetically-encoded fashion, enabling future work to define the LYTACable proteome.

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