Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 116, P. 117984 - 117984
Published: Nov. 8, 2024
Language: Английский
Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 176, P. 116910 - 116910
Published: June 8, 2024
Therapeutic proteins provided new opportunities for patients and high sales volumes. However, they are formulated extracellular targets. The lipophilic barrier of the plasma membrane renders vast array intracellular targets out reach. Peptide-based delivery systems, namely cell-penetrating peptides (CPPs), have few safety concerns, low immunogenicity, with control over administered doses. This study investigates CPP-based protein systems by classifying them into CPP-protein "covalent conjugation" CPP: "non-covalent complexation" categories. Covalent conjugates ensure proximity CPP to cargo, which can improve cellular uptake endosomal escape. We will discuss various aspects covalent through non-cleavable (stable) or cleavable bonds. Non-cleavable produced recombinant DNA technology express complete fusion in a host cell chemical ligation protein, ensures stability during process. bonds classified pH-sensitive redox-sensitive bonds, enzyme-cleavable physical stimuli linkers (light radiation, ultrasonic waves, thermo-responsive). highlighted key characteristics non-covalent complexes electrostatic hydrophobic interactions preserve conformational integrity cargo. CPP-mediated complexation, such as zippers, adaptor methods, avidin-biotin technology, featured. Conclusively, complexation methods appropriate when number samples be screened. In contrast, biological activity is critical compartment, conjugation protocols preferred.
Language: Английский
Citations
12
ACS Central Science, Journal Year: 2024, Volume and Issue: 10(5), P. 1033 - 1043
Published: April 17, 2024
Thiol-mediated uptake (TMU) is an intriguing enigma in current chemistry and biology. While the appearance of cell-penetrating activity upon attachment cascade exchangers (CAXs) has been observed by many increasingly being used practice, molecular basis TMU essentially unknown. The objective this study was to develop a general protocol decode dynamic covalent networks that presumably account for TMU. Uptake inhibition patterns obtained from removal exchange partners either protein knockdown or alternative inhibitors are aligned with original generated CAX transporters functions (here cell motility). These inclusive reveal four most significant CAXs known today enter cells along three almost orthogonal pathways. Epidithiodiketopiperazines (ETP) preferably integrins disulfide isomerases (PDIs), benzopolysulfanes (BPS) different PDIs, PDIA3, asparagusic acid (AspA), antisense oligonucleotide phosphorothioates (OPS) transferrin receptor can be activated PDIs their respective inhibitors. findings provide solid understand use enable prevent entry into cells.
Language: Английский
Citations
8
Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 367, P. 877 - 891
Published: Feb. 20, 2024
Language: Английский
Citations
6
Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 17, 2025
The nascent field of targeted protein degradation (TPD) could revolutionize biomedicine due to the ability degrader molecules selectively modulate disease-relevant proteins. A key limitation broad application TPD is its dependence on small-molecule ligands target proteins interest. This leaves unstructured or those lacking defined cavities for binding out scope many technologies. use proteins, peptides, and nucleic acids (otherwise known as "biologics") protein-targeting moieties in degraders addresses this limitation. In following sections, we provide a comprehensive critical review studies that have used peptides mediate hence functional control otherwise challenging targets. We describe existing platforms protein/peptide-based ligand identification drug delivery systems might be exploited biologic-based degraders. Throughout Review, underscore successes, challenges, opportunities using protein-based chemical biology tools spur discoveries, elucidate mechanisms, act new therapeutic modality.
Language: Английский
Citations
0
ACS Bio & Med Chem Au, Journal Year: 2025, Volume and Issue: 5(2), P. 268 - 282
Published: Feb. 27, 2025
Biologics such as proteins, peptides, and oligonucleotides are powerful ligands to modulate challenging drug targets that lack readily accessible "ligandable" pockets. However, the limited membrane permeance of biologics severely restricts their intracellular applications. Moreover, different cell types may exhibit varying levels impermeability, some delivery vehicles might be more sensitive this variance. Erythroid lineage cells especially deliver cargo because unique cytoskeleton absence endocytosis in mature erythrocytes. We recently employed a permeant miniature protein bioPROTACs human umbilical cord blood derived erythroid progenitor (HUDEP-2) primary hematopoietic stem (CD34+) (Shen et al., ACS Cent. Sci. 2022, 8, 1695−1703). While successful, low efficiency cell-type specificity limit use vivo. In work, we thoroughly evaluated performance various reported penetrating peptides (CPPs), CPP additives, bacterial toxins, contractile injection systems for ability precursor cells. also explored how targeting receptors enriched on surface improve efficiencies specificities these vehicles. Our results reveal certain improved when directed while others do not benefit from strategy. Together, findings advance our understanding illustrate intricacies cell-surface receptor targeting.
Language: Английский
Citations
0
Journal of Controlled Release, Journal Year: 2025, Volume and Issue: unknown, P. 113637 - 113637
Published: March 1, 2025
Language: Английский
Citations
0
Chemical Engineering Journal, Journal Year: 2024, Volume and Issue: 491, P. 152129 - 152129
Published: May 10, 2024
Language: Английский
Citations
3
Current Opinion in Chemical Biology, Journal Year: 2024, Volume and Issue: 81, P. 102482 - 102482
Published: June 20, 2024
Language: Английский
Citations
3
Brain Research, Journal Year: 2024, Volume and Issue: 1838, P. 148987 - 148987
Published: May 6, 2024
Dynamin is a microtubule (MT) binding protein playing key role in vesicle endocytosis. In brain slice model, tau loaded presynaptic terminals assembles MTs, thereby impairing endocytosis via depletion of cytosolic dynamin. The peptide PHDP5, derived from the pleckstrin homology domain dynamin 1, inhibits dynamin-MT interaction and rescues synaptic transmission impaired by when co-loaded terminals. We tested whether vivo administration PHDP5 could rescue their learning/memory deficits observed Alzheimer's disease (AD) model mice. A modified incorporating cell-penetrating (CPP) FITC fluorescent marker was delivered intranasally to Tau609 transgenic (Tg) 3xTg-AD FITC-positive puncta were hippocampus mice infused with or scrambled (SPHDP5) peptide, but not saline-infused controls. Morris water maze (MWM) test for spatial learning/memory, AD treated FITC-PHDP5-CPP showed prominent improvements learning memory, performing close level WT control. contrast, construct (FITC-SPHDP5-CPP) no significant improvement. conclude that can be candidate human therapy.
Language: Английский
Citations
1
Trends in Chemistry, Journal Year: 2024, Volume and Issue: unknown
Published: Oct. 1, 2024
Language: Английский
Citations
1