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Molecules (Basel, Switzerland) Dec 2020The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have... (Review)
Review
The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy.
Topics: Hydrophobic and Hydrophilic Interactions; Models, Molecular; Protein Binding; Small Molecule Libraries; Transcription Factors
PubMed: 33352993
DOI: 10.3390/molecules25246001 -
Frontiers in Oncology 2019Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumour in humans and has a very poor prognosis. The existing treatments have had... (Review)
Review
Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumour in humans and has a very poor prognosis. The existing treatments have had limited success in increasing overall survival. Thus, identifying and understanding the key molecule(s) responsible for the malignant phenotype of GBM will yield new potential therapeutic targets. The treatment of brain tumours faces unique challenges, including the presence of the blood brain barrier (BBB), which limits the concentration of drugs that can reach the site of the tumour. Nevertheless, several promising treatments have been shown to cross the BBB and have shown promising pre-clinical results. This review will outline the status of several of these promising targeted therapies.
PubMed: 31616641
DOI: 10.3389/fonc.2019.00963 -
Acta Tropica Jul 2021Podoconiosis is a non-filarial and non-communicable disease leading to lymphedema of the lower limbs. Worldwide, 4 million individuals live with podoconiosis, which is... (Review)
Review
Podoconiosis is a non-filarial and non-communicable disease leading to lymphedema of the lower limbs. Worldwide, 4 million individuals live with podoconiosis, which is accompanied by disability and painful intermittent acute inflammatory episodes that attribute to significant disability adjusted life years (DALYs). Different risk factors like contact with volcanic red clay soil, high altitude (above 1000 m), high seasonal rainfall (above 1000 mm/year) and occupation (e.g., subsistence farmer) are associated with the risk of podoconiosis. Although podoconiosis was described to be endemic in 32 countries in Africa, parts of Latin America and South East Asia, knowledge about related genetics, pathophysiology, immunology and especially the causing molecule(s) in the soil remain uncertain. Thus, podoconiosis can be considered as one of the most neglected diseases. This review provides an overview about this non-filarial related geochemical disease and aim to present perspectives and future directions that might be important for better understanding of the disease, prospect for point-of-care diagnosis, achieving protection and developing novel treatment strategies.
Topics: Elephantiasis; Humans; Risk Factors; Soil
PubMed: 33839086
DOI: 10.1016/j.actatropica.2021.105918 -
Biochemistry Apr 2020Messenger RNA degradation is an important component of overall gene expression. During the final step of eukaryotic mRNA degradation, exoribonuclease 1 (Xrn1) carries...
Messenger RNA degradation is an important component of overall gene expression. During the final step of eukaryotic mRNA degradation, exoribonuclease 1 (Xrn1) carries out 5' → 3' processive, hydrolytic degradation of RNA molecules using divalent metal ion catalysis. To initiate studies of the 5' → 3' RNA decay machinery in our lab, we expressed a C-terminally truncated version of Xrn1 and explored its enzymology using a second-generation, time-resolved fluorescence RNA degradation assay. Using this system, we quantitatively explored Xrn1's preference for 5'-monophosphorylated RNA substrates, its pH dependence, and the importance of active site mutations in the molecule's conserved catalytic core. Furthermore, we explore Xrn1's preference for RNAs containing a 5' single-stranded region both in an intermolecular hairpin structure and in an RNA-DNA hybrid duplex system. These results both expand and solidify our understanding of Xrn1, a centrally important enzyme whose biochemical properties have implications in numerous RNA degradation and processing pathways.
Topics: Exoribonucleases; Hydrogen-Ion Concentration; Models, Molecular; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 32251580
DOI: 10.1021/acs.biochem.9b01035 -
Molecules (Basel, Switzerland) Jul 2020Under healthy conditions, the cornea is an avascular structure which allows for transparency and optimal visual acuity. Its avascular nature is maintained by a balance... (Review)
Review
Under healthy conditions, the cornea is an avascular structure which allows for transparency and optimal visual acuity. Its avascular nature is maintained by a balance of proangiogenic and antiangiogenic factors. An imbalance of these factors can result in abnormal blood vessel proliferation into the cornea. This corneal neovascularization (CoNV) can stem from a variety of insults including hypoxia and ocular surface inflammation caused by trauma, infection, chemical burns, and immunological diseases. CoNV threatens corneal transparency, resulting in permanent vision loss. Mainstay treatments of CoNV have partial efficacy and associated side effects, revealing the need for novel treatments. Numerous natural products and synthetic small molecules have shown potential in preclinical studies in vivo as antiangiogenic therapies for CoNV. Such small molecules include synthetic inhibitors of the vascular endothelial growth factor (VEGF) receptor and other tyrosine kinases, plus repurposed antimicrobials, as well as natural source-derived flavonoid and non-flavonoid phytochemicals, immunosuppressants, vitamins, and histone deacetylase inhibitors. They induce antiangiogenic and anti-inflammatory effects through inhibition of VEGF, NF-κB, and other growth factor receptor pathways. Here, we review the potential of small molecules, both synthetics and natural products, targeting these and other molecular mechanisms, as antiangiogenic agents in the treatment of CoNV.
Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Corneal Neovascularization; Humans; Small Molecule Libraries
PubMed: 32751576
DOI: 10.3390/molecules25153468 -
Journal of Personalized Medicine Jan 2024The revolutionary progress in cancer immunotherapy, particularly the advent of immune checkpoint inhibitors, marks a significant milestone in the fight against... (Review)
Review
The revolutionary progress in cancer immunotherapy, particularly the advent of immune checkpoint inhibitors, marks a significant milestone in the fight against malignancies. However, the majority of clinically employed immune checkpoint inhibitors are monoclonal antibodies (mAbs) with several limitations, such as poor oral bioavailability and immune-related adverse effects (irAEs). Another major limitation is the restriction of the efficacy of mAbs to a subset of cancer patients, which triggered extensive research efforts to identify alternative approaches in targeting immune checkpoints aiming to overcome the restricted efficacy of mAbs. This comprehensive review aims to explore the cutting-edge developments in targeting immune checkpoints, focusing on both small molecule- and peptide-based approaches. By delving into drug discovery platforms, we provide insights into the diverse strategies employed to identify and optimize small molecules and peptides as inhibitors of immune checkpoints. In addition, we discuss recent advances in nanomaterials as drug carriers, providing a basis for the development of small molecule- and peptide-based platforms for cancer immunotherapy. Ongoing research focused on the discovery of small molecules and peptide-inspired agents targeting immune checkpoints paves the way for developing orally bioavailable agents as the next-generation cancer immunotherapies.
PubMed: 38248769
DOI: 10.3390/jpm14010068 -
Journal of Natural Products Jun 2023Fungal metabolites represent an underutilized resource in the development of novel anticancer drugs. This review will focus on the promising fungal nephrotoxin... (Review)
Review
Fungal metabolites represent an underutilized resource in the development of novel anticancer drugs. This review will focus on the promising fungal nephrotoxin orellanine, found in mushrooms including (Fools webcap). Emphasis will be placed on its historical significance, structural features, and associated toxicomechanics. Chromatographic methods for analysis of the compound and its metabolites, its synthesis, and chemotherapeutic potential are also discussed. Although orellanine's exceptional selectivity for proximal tubular cells is well documented, the mechanics of its toxicity in kidney tissue remains disputed. Here, the most commonly proposed hypotheses are detailed in the context of the molecule's structure, the symptoms seen following ingestion, and its characteristic prolonged latency period. Chromatographic analysis of orellanine and its related substances remains challenging, while biological evaluation of the compound is complicated by uncertainty regarding the role of active metabolites. This has limited efforts to structurally refine the molecule; despite numerous established methods for its synthesis, there is minimal published material on how orellanine's structure might be optimized for therapeutic use. Despite these obstacles, orellanine has generated promising data in preclinical studies of metastatic clear cell renal cell carcinoma, leading to the early 2022 announcement of phase I/II trials in humans.
Topics: Humans; Mycotoxins; Neoplasms; 2,2'-Dipyridyl; Agaricales
PubMed: 37308446
DOI: 10.1021/acs.jnatprod.2c01068 -
The Journal of Physical Chemistry. A Mar 2023Charge migration (CM) is a coherent attosecond process that involves the movement of localized holes across a molecule. To determine the relationship between a...
Charge migration (CM) is a coherent attosecond process that involves the movement of localized holes across a molecule. To determine the relationship between a molecule's structure and the CM dynamics it exhibits, we perform systematic studies of para-functionalized bromobenzene molecules (X-CH-R) using real-time time-dependent density functional theory. We initiate valence-electron dynamics by emulating rapid strong-field ionization leading to a localized hole on the bromine atom. The resulting CM, which takes on the order of 1 fs, occurs via an X localized → CH delocalized → R localized mechanism. Interestingly, the hole contrast on the acceptor functional group increases with increasing electron-donating strength. This trend is well-described by the Hammett σ value of the group, which is a commonly used metric for quantifying the effect of functionalization on the chemical reactivity of benzene derivatives. These results suggest that simple attochemistry principles and a density-based picture can be used to predict and understand CM.
PubMed: 36791088
DOI: 10.1021/acs.jpca.3c00568 -
International Journal of Physiology,... 2019Membrane fusion is a universal event in all living organism. It is at the heart of intracellular organelle biogenesis and membrane traffic processes such as endocytosis... (Review)
Review
Membrane fusion is a universal event in all living organism. It is at the heart of intracellular organelle biogenesis and membrane traffic processes such as endocytosis and exocytosis, and is also used by enveloped viruses to enter hosting cells. Regarding the cellular mechanisms underlying membrane fusion, pioneering studies by Randy Schekman, James Rothman, Thomas C. Südhof and their colleagues have demonstrated the function of specific proteins and protein-protein interactions as essential fusogenic factor to initiate membrane fusion. Since then, function of lipids and protein-lipid interaction has also been identified as important players in membrane fusion. Based on that NSF (NEM-sensitive factor where NEM stands for -ethyl-maleimide) and acyl-CoA are required for the membrane fusion of transporting vesicles with Golgi cisternae, it is further suggested that the transfer of the acyl chain to a molecule(s) is essential for membrane fusion. Among the previously identified fusogens, phosphatidic acid (PA) is found as an acyl chain recipient. Functionally, acylation of PA is required for tethering the membranes of Rab5a vesicles and early endosomes together during membrane fusion. As certain threshold of proximity between the donor and acceptor membrane is required to initiate membrane fusion, fusogenic factors beyond protein-protein and protein-lipid interaction need to be identified.
PubMed: 31993099
DOI: No ID Found