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Delivering peptides and proteins with intracellular function represents a promising avenue for therapeutics, but remains a challenge due to the selective permeability of the plasma membrane. The successful delivery of cytosolically active proteins would enable many opportunities, including improved vaccine development through major histocompatibility complex (MHC) class I antigen display. Extended research using cell-penetrating peptides (CPPs) has aimed to facilitate intracellular delivery of exogenous proteins with some success. A new class of polymer-based mimics termed protein transduction domain mimics (PTDMs), which maintain the positive charge and amphiphilic nature displayed by many CPPs, was developed using a poly-norbornene-based backbone. Herein, we use a previously characterized PTDM to investigate delivery of the model antigen SIINFEKL into leukocytes. Peptide delivery into over 90% of CD14+ monocytes was detected in less than 15 min with nominal inflammatory cytokine response and high cell viability. The co-delivery of a TLR9 agonist and antigen using the PTDM into antigen-presenting cells in vitro showed presentation of SIINFEKL in association with MHC class I molecules, in addition to upregulation of classical differentiation markers revealing the ability of the PTDM to successfully deliver cargo intracellularly and show application in the field of immunotherapy.
This article was published in the following journal.
Name: Molecular pharmaceutics
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A protein interaction domain of the death domain superfamily. It is characterized by a 6-helix bundle similar to those that occur in DEATH DOMAIN RECEPTORS. Pyrin domains are present in a variety of proteins, especially those that function in INFLAMMASOMES; AUTOPHAGY; and APOPTOSIS. They form homodimers or heterodimers with death domain proteins to facilitate the assembly of signaling complexes.
An SHC-signaling adaptor protein that links GROWTH FACTOR RECEPTORS to SIGNAL TRANSDUCTION PATHWAYS in neurons.
A highly conserved family of ATPases that facilitate the transport of lipids and cations across the plasma membrane. Structurally, they are elongated ALPHA-HELICES constituting five functionally distinct domains: three cytoplasmic domains A, N, and P which contain the catalytic sites, and two transmembrane domains. The N domain phosphorylates the P-domain at an invariant ASPARTATE residue, which, in turn, is dephosphorylated by the A domain. The phosphorylation and dephosphorylation cycles drive conformational changes in the protein between two states (E1 and E2), which allow the substrate to access the other side of the membrane.
A costimulatory ligand glycoprotein that contains a C2 and V-type IMMUNOGLOBULIN DOMAIN. It is expressed by ANTIGEN-PRESENTING CELLS and binds to CD28 ANTIGEN with high specificity and to CTLA-4 ANTIGEN with low specificity. The interaction of CD86 with CD28 ANTIGEN provides a stimulatory signal to T-LYMPHOCYTES, while its interaction with CTLA-4 ANTIGEN may play a role in inducing PERIPHERAL TOLERANCE.
A CD antigen that contains a conserved integrin I-domain which is involved in ligand binding. When combined with CD18 the two subunits form MACROPHAGE-1 ANTIGEN.
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