Single Posttranslational Modifications in the Central Repeat Domains of Tau4 Impact its Aggregation and Tubulin Binding.

A variety of methods have been employed to study the impact of posttranslational modifications on Tau protein function. Here, a semisynthesis strategy is described that enables selective modification within the central repeat domain of Tau4 (residues 291-321), comprising a major interaction motive with tubulin as well as one of the key hexapeptides involved in Tau aggregation. This strategy has led to the preparation of four semisynthetic Tau variants with phosphoserine residues in different positions and one with a so far largely ignored carboxymethyllysine modification that results from a non-enzymatic posttranslational modification (nPTM). The latter modification inhibits tubulin polymerization but exhibits an aggregation behavior very similar to unmodified Tau. In contrast, phosphorylated Tau variants exhibit similar binding to tubulin as unmodified Tau4 but show lower tendencies to aggregate.

Synthetic integrin-binding immune stimulators target cancer cells and prevent tumor formation.

Immuno-oncology approaches mainly utilize monoclonal antibodies or protein-based scaffolds that bind with high affinity to cancer cells and can generate an immune response. Peptides can also bind with high affinity to cancer cells and are intermediate in size between antibodies and small molecules. They are also synthetically accessible and therefore easily modified to optimize their stability, binding affinity and selectivity. Here we describe the design of immune system engagers (ISErs), a novel class of synthetic peptide-based compounds that bind specifically to cancer cells and stimulate the immune system. A prototype, Y9, targets integrin α3, which is overexpressed on several cancer cells, and activates the immune system via a formyl methionine-containing effector peptide. Injection of Y9 leads to immune cell infiltration into tissue and prevents tumor formation in a guinea pig model. The anti-tumor activity and synthetic accessibility of Y9 illustrate that ISErs could be applied to a wide variety of targets and diseases.