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Biochemistry Jan 2020
Topics: Intercellular Signaling Peptides and Proteins; Peptides; Proteolysis
PubMed: 31538467
DOI: 10.1021/acs.biochem.9b00795 -
Angewandte Chemie (International Ed. in... Mar 2024Many of the highest priority targets in a wide range of disease states are difficult-to-drug proteins. The development of reversible small molecule inhibitors for the... (Review)
Review
Many of the highest priority targets in a wide range of disease states are difficult-to-drug proteins. The development of reversible small molecule inhibitors for the active sites of these proteins with sufficient affinity and residence time on-target is an enormous challenge. This has engendered interest in strategies to increase the potency of a given protein inhibitor by routes other than further improvement in gross affinity. Amongst these, the development of catalytic protein inhibitors has garnered the most attention and investment, particularly with respect to protein degraders, which catalyze the destruction of the target protein. This article discusses the genesis of the burgeoning field of catalytic inhibitors, the current state of the art, and exciting future directions.
Topics: Proteins; Catalysis; Catalytic Domain; Proteolysis
PubMed: 38064411
DOI: 10.1002/anie.202316726 -
Trends in Biochemical Sciences Oct 2020
Topics: Mass Spectrometry; Proteins; Proteolysis
PubMed: 32475682
DOI: 10.1016/j.tibs.2020.05.006 -
Frontiers in Immunology 2023Phagosome acidification and proteolysis are essential processes in the immune response to contain and eliminate pathogens. In recent years, there has been an increased...
Phagosome acidification and proteolysis are essential processes in the immune response to contain and eliminate pathogens. In recent years, there has been an increased desire for a rapid and accurate method of assessing these processes in real-time. Here, we outline the development of a multiplexed assay that allows simultaneous monitoring of phagosome acidification and proteolysis in the same sample using silica beads conjugated to pHrodo and DQ BSA. We describe in detail how to prepare the bi-functional particles and show proof of concept using differentially activated macrophages. This multiplexed spectrophotometric assay allows rapid and accurate assessment of phagosome acidification and proteolysis in real-time and could provide valuable information for understanding the immune response to pathogen invasion.
Topics: Proteolysis; Macrophages; Biological Assay; Hydrogen-Ion Concentration; Phagosomes
PubMed: 37638042
DOI: 10.3389/fimmu.2023.1204223 -
Future Medicinal Chemistry Jan 2022Proteolysis-targeting chimeras (PROTACs) are a powerful tool to hijack the endogenous ubiquitin-proteasome system (UPS) and to degrade the intracellular proteins of... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) are a powerful tool to hijack the endogenous ubiquitin-proteasome system (UPS) and to degrade the intracellular proteins of therapeutic importance. Recently, two heterobifunctional degraders targeting hormone receptors headed into phase II clinical trials. Compared to traditional drug design and common modes of action, the PROTAC approach offers new opportunities for the drug research field. Histone deacetylase inhibitors (HDACi) are well-established drugs for the treatment of hematological malignancies. The integration of HDAC binding motifs in PROTACs explores the possibility of targeted, chemical HDAC degradation. This review provides an overview and a perspective about the key steps in the structure development of HDAC-PROTACs. In particular, the influence of the three canonical PROTAC elements on HDAC-PROTAC efficacy and selectivity are discussed, the HDACi, the linker and the E3 ligase ligand.
Topics: Drug Design; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Molecular Conformation; Proteolysis
PubMed: 34951318
DOI: 10.4155/fmc-2021-0206 -
Molecules (Basel, Switzerland) Aug 2022Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively... (Review)
Review
Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.
Topics: Drug Development; Immunotherapy; Neoplasms; Proteolysis
PubMed: 36080223
DOI: 10.3390/molecules27175439 -
ChemMedChem Jul 2020Proteolysis targeting chimeras, PROTACs, are emerging as a powerful strategy for exerting exogenous control over protein levels, allowing small molecules to exploit the... (Review)
Review
Proteolysis targeting chimeras, PROTACs, are emerging as a powerful strategy for exerting exogenous control over protein levels, allowing small molecules to exploit the ubiquitin-proteasome pathway for targeted protein degradation. This highlight focuses on the fusion of photochemistry with these bifunctional compounds, which has provided a novel pathway for spatiotemporally tuning the activation of PROTACs in the form of their photocaged and photoswitchable versions. Photocaged PROTACs consist of a hindered optolabile group that detaches only upon irradiation at a specific wavelength, releasing the active PROTAC. These modified PROTACs are inactive in the dark. Photoswitchable PROTACs are photoisomerizable molecules with azobenzene linkages that are active in either the cis or trans form and inactive in the other. The isomers interconvert upon irradiation with an appropriate wavelength of light and relax to the thermodynamically stable isomer in the dark or with another wavelength of light. Although photocaged PROTACs only permit activation control for protein degradation, photoswitching PROTACs offer reversible activation and deactivation by using suitable wavelengths of light.
Topics: Light; Molecular Structure; Photochemical Processes; Proteolysis; Small Molecule Libraries; Thermodynamics
PubMed: 32558301
DOI: 10.1002/cmdc.202000249 -
Journal of Food Biochemistry Sep 2020To explore the immunoregulatory function of peony seed proteolysis product in mice, the protein from peony seed meal was extracted and hydrolyzed with bromelain. The...
To explore the immunoregulatory function of peony seed proteolysis product in mice, the protein from peony seed meal was extracted and hydrolyzed with bromelain. The peony seed proteolysis product was fed to mice at three different doses of 0.25, 0.5, and 1.0 g/kg for 21 days. The immunoregulation abilities of peony seed proteolysis product after each of these doses were evaluated in mice. Our results showed that all immune indices were higher in mice that had received a lavage with peony seed proteolysis product than in control mice. The immune indices of immune organs, delayed-type hypersensitivity reaction (DTH), phagocytosis of peritoneal macrophages, serum hemolysin levels, lymphocyte proliferation (SI value), and levels of IFN-γ and IL-4 in the middle dose and high dose groups were significantly higher (p < .05) or extremely significant (p < .01) in comparison with the control group. These results indicate that the peony seed proteolysis product enhances immunological functions in mice. PRACTICAL APPLICATIONS: Peony seed is rich in proteins and can be extracted and hydrolyzed using bromelain. The peony seed proteolysis product can enhance the nonspecific, humoral, and cellular immune responses. Thus, peony seed could be of potential value to obtain peony seed protein, which can be further developed and utilized in the manufacture of functional health products.
Topics: Animals; Mice; Paeonia; Proteolysis; Seeds
PubMed: 32614083
DOI: 10.1111/jfbc.13353 -
Drug Discovery Today Feb 2022Selective chemical modulators are ideal tools to study the function of a protein. Yet, the poor ligandability of many proteins has hampered the development of specific... (Review)
Review
Selective chemical modulators are ideal tools to study the function of a protein. Yet, the poor ligandability of many proteins has hampered the development of specific chemical probes for numerous protein classes. Tools, such as covalent inhibitors and activity-based protein profiling, have enhanced our understanding of thus-far difficult-to-target proteins and have enabled correct assessment of the selectivity of small-molecule modulators. This also requires deeper knowledge of compound and target site reactivity, evaluation of binding to noncovalent targets and protein turnover. The availability of highly selective chemical probes, the evolution of activity-based probes, and the development of profiling methods will open a new era of drugging the undruggable proteome.
Topics: Proteolysis; Proteome
PubMed: 34728376
DOI: 10.1016/j.drudis.2021.10.021 -
Current Opinion in Chemical Biology Apr 2022Challenging disease targets necessitate new approaches for therapeutic intervention. Rewiring protein-biomolecule interactions with proximity-inducing agents extends... (Review)
Review
Challenging disease targets necessitate new approaches for therapeutic intervention. Rewiring protein-biomolecule interactions with proximity-inducing agents extends intervention opportunities beyond target agonism or inhibition. Spanning varied molecular phenotypes and diverse target classes, proximity-inducing agents demonstrate immense potential across target degradation, cleavage, and post-translational editing. Here, we review a selection of exciting developments in the concepts and mechanisms of induced proximity-driven strategies from the last two years. Key technological advances that enable these discoveries and expand the scope of targets and machinery for induced-proximity modalities are highlighted.
Topics: Protein Processing, Post-Translational; Proteolysis; Proteomics
PubMed: 35033823
DOI: 10.1016/j.cbpa.2021.102107