Chiral Protein Supraparticles for Tumor Suppression and Synergistic Immunotherapy: An Enabling Strategy for Bioactive Supramolecular Chirality Construction

Abstract

The design of bioactive supramolecular chirality is always hampered by the lack of feasible schemes to assigned specific biological activities. Herein, we developed a “mirror-image peptide grafting” method to graft the epitopes of bioactive d-peptide onto the miniprotein template to construct a self-assembled supraparticle. Grafting DPMIβ, a 12-mer d-enantiomeric peptide functioned as the p53 agonist, onto Apamin, we successfully constructed a self-assembled d-enantiomeric miniprotein supermolecule nanoparticle, termed DMSN. This chiral supraparticle possesses a favorable pharmaceutical profile including the passive tumor targeting, cell membrane penetration, intracellular reductive responsiveness, and endosome escaping. DMSN showed in vitro and in vivo p53-dependent antiproliferative activity and augmented antitumor immunity elicited by anti-PD1 therapy. This enabling strategy will allow us to fabricate a class of peptide/protein-derived supramolecular chirality with predictable biological activities and will likely have a broad impact on the chiral nanotechnology at the service of prevention and treatment of human diseases.

De Novo Nano‐Erythrocyte Structurally Braced by Biomimetic Au(I)‐peptide Skeleton for MDM2/MDMX Predation toward Augmented Pulmonary Adenocarcinoma Immunotherapy

“…In this proof-of-concept research, a ternary fusion peptide termed PMIV was selected to fabricate the bionic cytoskeleton. PMIV was designed to concatenate the targeting protein MDM2/MDMX with the E3 ubiquitin convener VHL, and it contained three functional fragments: 1) a high-affinity and dual-specificity dodecameric motif (PMI) binding to MDM2 and MDMX at the amino terminal, [31][32][33][34][35] 2) a hydroxyprolineand homoleucine-containing octapeptide (VBP) recognized by the VHL at the carboxyl terminal, [36] and 3) a flexible PEG pentamer linker connecting PMI and VBP. Of note, an extra cysteine residue was extended to the C-terminus of PMIV for nanocluster formation.…”

Turing milk into pro-apoptotic oral nanotherapeutic: De novo bionic chiral-peptide supramolecule for cancer targeted and immunological therapy

“…Fortunately, the favorable proteolysis resistance endows D-peptides with the capacity to withstand the multi-protease environment in digestive tract 11 , 12 , yielding the precondition for oral administration. Even so, oral dosage is difficult for them, because the absorption of D-enantiomeric peptides from gut into circulation remains a formidable obstacle 13 , 14 .…”

“…In this case, kinetics characteristics of the drug can be changed, allowing the preferential cellular uptakes through endocytosis or micropinocytosis 33 - 35 . Thus, turning D-peptides into a well-defined nanomedicine is a feasible method to realize the efficient cellular internalization 12 , 36 , 37 . As for the nanofabrication techniques, some chiral biological nanostructures have been produced by lithography and molecular self-assembly 2 , 38 , 39 , but it is remaining a challenge to reliably fabricate three-dimensional chiral peptide-derived nanostructures on a large scale.…”

Molecular dynamics simulation approach for discovering potential inhibitors against SARS-CoV-2: A structural review

“…The genome of SARS-CoV-2 encrypts structural molecules including S (spike glycoprotein), E (envelope), M (membrane), and N (nucleocapsid), as well as non-structural components as with M pro , papain-like protease (PLP), and RNA dependent RNA polymerase (RdRp). The transcription and replication cycle occur due to the non-structural proteins, while structural proteins are mainly liable for interactions with human organisms during the entrance process of the virus [5] , [6] , [7] , [8] . Viral RdRp is responsible for speeding up the replication of RNA which 97.08 % of its sequence has been partaken with SARS‐CoV [9] .…”