The biology and regulation of YAP and TAZ, two closely related transcriptional regulators, are receiving increasing attention owing to their fundamental roles in organ growth, tissue repair and cancer. In particular, the widespread activation of YAP/TAZ in carcinomas, and the crucial role of YAP/TAZ activation for many 'hallmarks' of cancer are indicating YAP/TAZ as prime targets for designing anti-cancer drugs. Here, we start from the known modalities to regulate YAP/TAZ to highlight possible routes of therapeutic intervention.
It is increasingly being appreciated that GABA receptor subtypes, through their specific regional, cellular and subcellular localization, are linked to distinct neuronal circuits and consequently serve distinct functions. GABA receptor subtype-selective drugs are therefore expected to provide novel pharmacological profiles. Receptors containing the α subunit mediate sedation and serve as targets for sedative hypnotics. Agonists selective for α2- and/or α3-containing GABA receptors have been shown to provide anxiolysis without sedation in preclinical models, whereas inverse agonists selective for α5-containing GABA receptors provide memory enhancement. Agonists selective for α3-containing GABA receptors might be suitable for the treatment of deficits in sensorimotor processing in psychiatric disorders. Thus, a new pharmacology based on GABA receptor subtype-specific actions is emerging.
Gabapentin and pregabalin are structurally related compounds with recognized efficacy in the treatment of both epilepsy and neuropathic pain. The pharmacological mechanisms by which these agents exert their clinical effects have, until recently, remained unclear. The interaction of gabapentin and pregabalin with conventional antiepileptic and analgesic drug targets is likely to be modest, at best, and has been largely dismissed in favour of a selective inhibitory effect on voltage-gated calcium channels containing the alpha(2)delta-1 subunit. This mechanism is consistently observed in both rodent- and human-based experimental paradigms and may be sufficiently robust to account for much of the clinical activity of these compounds.
Transcription factors (TFs) are very attractive but difficult drug targets. The difficulties come from several directions including the binding promiscuity of TFs and the intrinsically disordered nature of their binding sites, which often resemble ‘protein clouds’. For a long time the targeting of proteins without defined structures was considered infeasible. Data have now emerged showing that selective blocking of specific interactions of intrinsically disordered TFs with their protein binding partners is possible. Initial hits have been optimized to increase their specificity and affinity. Several strategies have been elaborated for elucidating the mechanisms of blocking of intrinsic disorder-based protein–protein interactions. However, challenges remain in the field of drug development for ‘protein clouds’; such development is still in its earliest stage.
Fecal microbiota transplantation (FMT) represents the most effective means of therapeutically manipulating the gastrointestinal microbiome. Originally employed as a treatment of last-resort in patients with life-threatening infection (CDI), FMT gained widespread acceptance during the CDI epidemic, where it achieved resolution rates approaching 100%. Following our newfound appreciation for the role of the gut microbiome in both health and disease and owing to FMT’s unique mechanism/s of action, FMT is rapidly advancing as an effective treatment for a number of conditions in which the gastrointestinal microbiome is thought to play a role. We review the role of FMT from its beginnings in CDI to its expansion into inflammatory bowel disease, irritable bowel syndrome, and colon cancer.
The use of and interest in probiotics to modulate the human intestinal microbiota have strongly increased in recent years. However, most of the current probiotic products have been limited to single-strain formulations of easily culturable food-grade microorganisms and often resulted in mixed results or limited effects on host health. Therefore, a revision of current probiotic strategies by using synthetic human-derived microbial multispecies consortia is necessary. In light of this ongoing evolution of the field, novel approaches are needed to design and assemble bacterial cocktails targeted to restore dysbiotic states in microbiota-associated diseases. This review discusses the steps in the process for identifying effective targets, predicting putative multistrain communities, assembling ecosystems and and monitoring stability and outputs before trials.
Research in the field of gut microbiota – brain axis may contribute to clarifying the origin of anorexia nervosa and bulimia, the two principal forms of eating disorders (ED). The initial key findings in ED patients of plasma immunoglobulins (Ig) that react with α-melanocyte-stimulating hormone (α-MSH), a neuropeptide in the brain signaling satiety, have initiated further studies leading to the discovery of the origin of such autoantibodies and to the understanding their possible functional role. An anorexigenic bacterial protein caseinolytic protease B was recently found to be responsible for the production of α-MSH-cross-reactive autoantibodies and this protein was also detected in human plasma. Another recent study revealed enhanced activation of appetite-regulating the melanocortin type 4 receptor by immune complexes with α-MSH. Taken together, these data serve to build a pathophysiological model of ED presented in this article.
My thesis is a simple one. We have not been doing a good enough job selecting dose regimens for serious infections during the drug development process. If we are to do a better job in the future, we need to revisit some uncomfortable places. That is, some notable program failures. To be clear, we are not revisiting program failures to make anyone uncomfortable or cast aspersions — but rather so that we sow the seeds for a better future. To that end, we will examine program failures and successes through a pharmacometric lens. Through this powerful lens, we will come to understand that many of our failures were not only predictable, but perhaps expected and entirely avoidable. The goal of this communication is to set forth the type of thinking and data that is necessary for rational dose selection.
Among the targets for the development of new antibacterial agents, bacterial topoisomerases remain a vibrant area of discovery. A structurally diverse set of inhibitors that bind to the adenosine 5'-triphosphate (ATP) site of type II topoisomerases have been disclosed recently. Seven compounds with this mechanism are highlighted, focusing on antibacterial potency and spectrum, as well as examples of in vivo efficacy against pathogens including Staphylococcus aureus and Mycobacterium tuberculosis. Five compounds from two structural classes are exemplified that are inhibitors that bind to the catalytic site of DNA gyrase and topoisomerase IV. The pharmacokinetic and pharmacodynamic properties of these molecules, derived from in vivo efficacy against Gram-positive and Gram-negative pathogens, define the potential for these agents with broad-spectrum and targeted-spectrum clinical utilities.
These are exciting times in the development of therapeutics for cystic fibrosis (CF). New correctors and potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) are being developed in academic laboratories and pharmaceutical companies, and the field is just beginning to understand their mechanisms of action. Studies of CFTR modulators are also yielding insight into the general principles and strategies that can be used when developing pharmacological chaperones, a new class of drugs. Combining two or even three correctors with a potentiator is an especially promising approach which should lead to further improvements in efficacy and clinical benefit for patients.
Unlike conventional cancer therapeutics, death receptor ligands trigger tumor cell apoptosis independently of the p53 tumor suppressor gene, which frequently is inactivated in cancer. The death receptor ligand Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) offers promising therapeutic potential based on its ability to induce apoptosis in various cancer cell lines with little toxicity toward normal cells. Moreover, Apo2L/TRAIL displays single-agent activity and cooperates with chemotherapy or radiotherapy in a variety of tumor xenograft mouse models. Thus, Apo2L/TRAIL might be effective against tumors that have acquired resistance to conventional therapy, and could augment the efficacy of current treatment in a wide spectrum of cancers.
The search for medications to treat prion diseases has lasted more than 30 years but no clinically validated treatments for prion diseases of humans or livestock have been realized. A primary strategy has been to identify molecules that can inhibit the formation of pathological forms of prion protein, for example, protease-resistant forms called PrP . Such inhibitors can prolong the lives of experimental animals inoculated peripherally with prions, but the practical therapeutic efficacy of known inhibitors against ongoing brain infections has so far been limited by toxicity, insufficient bioavailability to the CNS, and/or strain specificities. Thus, the search continues for clinically applicable inhibitors of PrP accumulation. Here we highlight key cell-free assays that are useful for the initial screening and mechanistic characterization of such compounds and are relatively high throughput, rapid, and cost-effective. These include cell-free conversions, protein misfolding cyclic amplification (PMCA), real time quaking-induced conversion (RT-QuIC), and fluorescence correlation-based competitive binding assays.
The human glutathione S-transferase, GSTs, possess both enzymatic and non-enzymatic functions and are involved in many important cellular processes, such as, phase 11 metabolism, stress response, cell proliferation, apoptosis, oncogenesis, tumor progression and drug resistance. The nonenzymatic functions of GSTs involve their interactions with cellular proteins, such as, JNK, TRAF, ASK, PKC, and TGM2, during which, either the interacting protein partner undergoes functional alteration or the GST protein itself is post-translationally modified and/or functionally altered. The majority of GST genes harbor polymorphisms that influence their transcription and/or function of their encoded proteins. This overview focuses on recent insights into the biology and pharmacogenetics of GSTs as a determinant of cancer drug resistance and response of cancer patients to therapy.