Supramolecular Toxin Complexes for Targeted Pharmacological Modulation of Polymorphonuclear Leukocyte Functions

Abstract

The targeted pharmacological modulation of polymorphonuclear leukocytes (PMNs) is of major medical interest. These innate immune cells play a central role in the defense against pathogenic microorganisms. However, their excessive chemotactic recruitment into tissues after traumatic injury is detrimental due to local and systemic inflammation. Rho‐GTPases, being the master regulators of the actin cytoskeleton, regulate migration and chemotaxis of PMNs, are attractive pharmacological targets. Herein, supramolecular protein complexes are assembled in a “mix‐and‐match” approach containing the specific Rho‐inhibiting clostridial C3 enzyme and three PMN‐binding peptides using an avidin platform. Selective delivery of the C3 Rho‐inhibitor with these complexes into the cytosol of human neutrophil‐like NB‐4 cells and primary human PMNs ex vivo is demonstrated, where they catalyze the adenosine diphosphate (ADP) ribosylation of Rho and induce a characteristic change in cell morphology. Notably, the complexes do not deliver C3 enzyme into human lung epithelial cells, A549 lung cancer cells, and immortalized human alveolar epithelial cells (hAELVi), demonstrating their cell type‐selectivity. The supramolecular complexes represent attractive molecular tools to decipher the role of PMNs in infection and inflammation or for the development of novel therapeutic approaches for diseases that are associated with hyperactivity and reactivity of PMNs such as post‐traumatic injury.

Supramolecular Hunter Stationed on Red Blood Cells for Detoxification Based on Specific Molecular Recognition

“…WP6@JDA@RBC could enduringly patrol in circulation, hunt paraquat in plasma, and facilely reach the polluted organs (Figure S15A). Because the WP6/paraquat couple had a much higher host−guest complexation constant than WP6/pyridinium, through a noncovalent guest-exchange reaction, 33 paraquat could be captured by WP6 to form a stable complex (Figure 5H) with much less ROS toxicity.…”

Solid‐Phase Protein Modifications: Towards Precision Protein Hybrids for Biological Applications

“…The strong noncovalent interaction of avidin‐biotin has been exploited extensively in molecular biology and sensing, and avidin has been used as a bioadaptor for heterofunctional bioconjugates especially in cancer pre‐targeting. Precise control of the resultant stoichiometry and spatial orientation of the conjugates is limited using chemical methods and despite attempts to engineer monovalent or divalent streptavidin proteins by genetic engineering to manipulate the stoichiometry, the applications are still hampered by lower binding constants [15] and a lack of spatial control. To alleviate this problem, solid‐phase strategies have been devised to modify avidin bioadaptors toposelectively.…”

“…Nevertheless, synthetic methods are highly valuable as complementary tools to genetic engineering and could be employed to overcome the limitations of the functional groups presented by 20 proteinogenic amino acids and offer the possibility to program external stimuli such as pH or light triggers to evolve the proteins beyond their natural functions [10–12] . Such strategies hold immense value for the advancement of synthetic biology and personalized medicine through the expansion of Nature's repertoire with unlimited synthetic combination [13–15] . Therefore, the development of synthetic tools that allow chemical modifications in site‐directed manner and self‐assembly of chemically modified proteins under mild conditions to surmount the challenges of selectivity and precision is necessary for the innovation of next generation therapeutics and diagnostics.…”

Assembly of pH‐Responsive Antibody‐Drug‐Inspired Conjugates

“…[ 19 ] In this regards, we have previously established the assembly of multiprotein complexes that contain functional proteins as well as multiple copies of targeting peptides on an avidin to target cancer cells that overexpress somatostatin 2 receptors (SSTR2). [ 20–22 ] The chemically engineered fusion protein has shown significant improvement for cell‐type selective antitumor treatment compared to treatment with the antibody, avastin. [ 20 ]…”