Targeting of extracellular protein-protein interactions with macrocyclic peptides.

Targeting of extracellular protein-protein interactions (PPI) is emerging as a major application for de novo discovered macrocyclic peptides. Modern discovery platforms can routinely identify macrocyclic peptide ligands capable of highly selective modulation of extracellular signaling pathways; amenability to chemical synthesis and natural modularity of peptides additionally provides an avenue for their further structural elaboration, while the challenge of cell internalization can be minimized. Here, we discuss the recent progress in targeting extracellular PPIs with macrocyclic peptides by focusing on a number of recent case studies.

Formation of the High-Spin S State Related to the Extrinsic Proteins in the Oxygen Evolving Complex of Photosystem II.

The high-spin S state was investigated with photosystem II (PSII) from spinach, , and . In extrinsic protein-depleted PSII, high-spin electron paramagnetic resonance (EPR) signals were not detected in either species, whereas all species showed ∼ 5 signals in the presence of a high concentration of Ca instead of the multiline signal. In the intact and PsbP/Q-depleted PSII from spinach, the = 4.

Molecular Structure of the S State with a = 5 Signal in the Oxygen Evolving Complex of Photosystem II.

The -factor shift of the = 4.1 EPR signal was detected in spinach PsbO/P/Q-depleted PS II. The effective -factor of the signal shifts up to ∼4.

Valosin-containing Protein is a Target of 5'-l Fuligocandin B and Enhances TRAIL Resistance in Cancer Cells.

Fuligocandin B () is a novel natural product that can overcome TRAIL resistance. We synthesized enatiomerically pure fuligocandin B () and its derivative 5'-I fuligocandin B (), and found that the latter had an improved biological activity against the human gastric cancer cell line, AGS. We attached a biotin linker and photoactivatable aryl diazirine group to 5'-I fuligocandin B (), and employed a pull-down assay to identify valosin-containing protein (VCP/p97), an AAA ATPase, as a 5'-I fuligocandin B () target protein.