Use Of Small Molecule Drugs Research Articles

Challenges and opportunities of developing small-molecule therapies for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of vision loss in senior adults. The disease can be categorized into two types: wet AMD and dry AMD. Wet AMD, also known as exudative or neovascular AMD, is less common but more severe than dry AMD and is responsible for 90% of the visual impairment caused by AMD and affects 20 million people worldwide. Current treatment options mainly involve biologics that inhibit the vascular endothelial growth factor or complement pathways. However, these treatments have limitations such as high cost, injection-related risks, and limited efficacy. Therefore, new therapeutic targets and strategies have been explored to improve the outcomes of patients with AMD. A promising approach is the use of small-molecule drugs that modulate different factors involved in AMD pathogenesis, such as tyrosine kinases and integrins. Small-molecule drugs offer advantages, such as oral administration, low cost, good penetration, and increased specificity for the treatment of wet and dry AMD. This review summarizes the current status and prospects of small-molecule drugs for the treatment of wet AMD. These advances are expected to support the development of effective and targeted treatments for patients with AMD.

Designing combinational herbal drugs based on target space analysis.

Traditional oriental medicines (TOMs) are a medical practice that follows different philosophies to pharmaceutical drugs and they have been in use for many years in different parts of the world. In this study, by integrating TOM formula and pharmaceutical drugs, we performed target space analysis between TOM formula target space and small-molecule drug target space. To do so, we manually curated 46 TOM formulas that are known to treat Anxiety, Diabetes mellitus, Epilepsy, Hypertension, Obesity, and Schizophrenia. Then, we employed Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties such as human ether-a-go-go related gene (hERG) inhibition, Carcinogenicity, and AMES toxicity to filter out potentially toxic herbal ingredients. The target space analysis was performed between TOM formula and small-molecule drugs: (i) both are known to treat the same disease, and (ii) each known to treat different diseases. Statistical significance of the overlapped target space between the TOM formula and small-molecule drugs was measured using supportvalue. Support value distribution from randomly selected target space was calculated to validate the result. Furthermore, the Si-Wu-Tang (SWT) formula and published literature were also used to evaluate our results. This study tried to provide scientific evidence about the effectiveness of the TOM formula to treat the main indication with side effects that could come from the use of small-molecule drugs. The target space analysis between TOM formula and small-molecule drugs in which both are known to treat the same disease shows that many targets overlapped between the two medications with a support value of 0.84 and weighted average support of 0.72 for a TOM formula known to treat Epilepsy. Furthermore, support value distribution from randomly selected target spacesin this analysis showed that the number of overlapped targets is much higher between TOM formula and small-molecule drugs that are known to treat the same disease than in randomly selected target spaces. Moreover, scientific literature was also used to evaluate the medicinal efficacy of individual herbs. This study provides an evidence to the effectiveness of a TOM formula to treat the main indication as well asside effects associated with the use of pharmaceutical drugs, as demonstrated through target space analysis.

Novel N-(3-ethynyl Phenyl)-6,7-bis(2-methoxyethoxy)Quinazoline-4-amine Derivatives: Synthesis, Characterization, Anti-cancer Activity, In-silico and DFT Studies.

Cancer is one of the most common reasons for mortality in the world. A continuous effort to develop effective anti-cancer drugs with minimum side effects has become necessary. The use of small-molecule drugs has revolutionized cancer research by inhibiting cancer cell survival and proliferation. Quinazolines are a class of bioactive heterocyclic compounds with active pharmacophores in several anti-cancer drugs. Such small molecule inhibitors obstruct the significant signals responsible for cancer cell development, thus blocking these cell signals to prevent cancer development and spread. In the current study, novel quinazoline derivatives structurally similar to erlotinib were synthesized and explored as novel anti-cancer agents. All the synthesized molecules were confirmed by spectroscopic techniques like 1H NMR, 13C NMR, and ESI-MS. Various techniques were applied to study the protein-drug interaction, DFT analysis, Hirshfeld surface, and target prediction. The molecules were screened in vitro for their anti-cancer properties against 60 human tumor cell lines. The growth inhibitory properties of a few compounds were studied against the MCF7 breast cancer cell line. The activity of compounds 9f, 9o, and 9s were found to be active. However, compound 9f is more active when compared with other compounds. Some synthesized compounds were active against different cancer cell lines. The in-vitro study results were found to be in agreement with the predictions from in-silico data. The selected molecules were further subjected to get the possible mechanism of action against different cancer cells.

Review article: Risk of cardiovascular events in patients with inflammatory bowel disease receiving small molecule drugs.

In the context of an ageing inflammatory bowel disease (IBD) population, cardiovascular comorbidities become particularly relevant. Novel small molecule drugs (SMDs) for the treatment of moderate-to-severe IBD have been recently approved, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor (S1P) modulators. Data from rheumatoid arthritis population have raised concerns about the risk of cardiovascular events with the use of tofacitinib, which was extrapolated to other immune-mediated diseases and other JAK inhibitors. S1P receptor modulation has been associated with potential cardiovascular events, especially bradycardia and cardiac conduction abnormalities. To review the incidence of cardiovascular events with the use of SMDs in patients with IBD and to provide practical recommendations on mitigation strategies. Published literature was reviewed; recommendations were synthesised by experts in both cardiovascular diseases and IBD. Evidence from the IBD population does not indicate a higher risk of cardiovascular events with tofacitinib and other JAK inhibitors. The risk is higher in patients with intermediate to high cardiovascular risk. S1P modulators may be associated with a dose-dependent, first-dose effect, transient risk of conduction abnormalities (bradycardia and AV block). Screening and monitoring of cardiovascular risk factors should be done in all patients with IBD. Risk stratification for cardiovascular disease should be performed before starting treatment with SMDs. Available evidence of both JAK inhibitors and S1P modulators indicates a reassuring safety profile of SMDs from the cardiovascular perspective in the overall IBD population. Efforts should be made to identify patients with IBD at a higher risk of cardiovascular events.

Impact of cholesterol and Lumacaftor on the folding of CFTR helical hairpins

Cystic fibrosis (CF) is caused by mutations in the gene that codes for the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR). Recent advances in CF treatment have included use of small-molecule drugs known as modulators, such as Lumacaftor (VX-809), but their detailed mechanism of action and interplay with the surrounding lipid membranes, including cholesterol, remain largely unknown. To examine these phenomena and guide future modulator development, we prepared a set of wild type (WT) and mutant helical hairpin constructs consisting of CFTR transmembrane (TM) segments 3 and 4 and the intervening extracellular loop (termed TM3/4 hairpins) that represent minimal membrane protein tertiary folding units. These hairpin variants, including CF-phenotypic loop mutants E217G and Q220R, and membrane-buried mutant V232D, were reconstituted into large unilamellar phosphatidylcholine (POPC) vesicles, and into corresponding vesicles containing 70 mol% POPC +30 mol% cholesterol, and studied by single-molecule FRET and circular dichroism experiments. We found that the presence of 30 mol% cholesterol induced an increase in helicity of all TM3/4 hairpins, suggesting an increase in bilayer cross-section and hence an increase in the depth of membrane insertion compared to pure POPC vesicles. Importantly, when we added the corrector VX-809, regardless of the presence or absence of cholesterol, all mutants displayed folding and helicity largely indistinguishable from the WT hairpin. Fluorescence spectroscopy measurements suggest that the corrector alters lipid packing and water accessibility. We propose a model whereby VX-809 shields the protein from the lipid environment in a mutant-independent manner such that the WT scaffold prevails. Such ‘normalization’ to WT conformation is consistent with the action of VX-809 as a protein-folding chaperone.

Self-assembling branched amphiphilic peptides for targeted delivery of small molecule anticancer drugs

Water insolubility poses a significant challenge in the clinical applications of many small molecule drugs. To improve the drug delivery efficiency, two branched amphiphilic peptides (BAPs) were designed in a computer-aided manner, for drug-loading through peptide self-assembling. The structures of the two BAPs, bis(LVFFA)-K-RGD (PepV-1) and bis(FHF)-K-RGD (PepV-2), were inspired by phospholipids, containing the RGD sequence as the hydrophilic head and two hydrophobic sequences as the hydrophobic tails. PepV-1 could self-assemble into nano-fibrils with a hydrophobic core and the RGD moiety on the surface. Its drug-loading efficiency (DE%) of three small molecule anticancer drugs (doxorubicin, camptothecin and curcumin) ranged from 9.90% to 11.74%, and entrapment efficiency (EE%) ranged from 37.30% to 43.00%. Pep-V2 could self-assemble into bilayer delimited nano-vesicles. The DE% of PepV-2 for these drugs ranged from 15.87% to 18.55%, and the EE% ranged from 60.45% to 73.23%. Both BAP carriers could prolong the release of the small molecule drugs, and the PepV-2 vesicles also showed pH-triggered increase of drug release due to the histidine residues. Bothe BAP carriers could increase the cytotoxicity against cancer cells, which might be due to the targeting on the cancer overexpressed integrins. The designed BAP carriers represent promising functional drug carriers for targeted drug delivery, and will be useful for improving the clinical use of small molecule drugs, especially for those with poor water solubility.

PBPK modelling to predict drug-biologic interactions with cytokine modulators: Are these relevant and is IL-6 enough?

Drugs that modulate cytokine levels are often used for the treatment of cancer as well as inflammatory or immunological disorders. Pharmacokinetic drug-biologic interactions (DBI) may arise from suppression or elevation of cytochrome P450 (CYP) enzymes caused by the increase or decrease in cytokine levels following administration of these therapies. There is in vitro and in vivo evidence that demonstrates a clear link between raised interleukin (IL)-6 levels and CYP suppression, in particular CYP3A4. However despite this, the changes in IL-6 levels in vivo rarely lead to significant drug interactions (AUC and Cmax ratios < 2-fold). The clinical significance of such interactions therefore remains questionable and is dependent on the therapeutic index of the small molecule therapy. Physiologically-based pharmacokinetic (PBPK) modelling has been used successfully to predict the impact of raised IL-6 on CYP activities. Beyond IL-6, published data show little evidence that IL-8, IL-10, and IL-17 suppress CYP enzymes. I n vitro data suggest that IL-1β, IL-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ can cause suppression of CYP enzymes. Despite in vivo there being a link between IL-6 levels and CYP suppression, the evidence to support a direct effect of IL-2, IL-8, IL-10, IL-17, IFN-γ, TNF-α or vascular endothelial growth factor (VEGF) on CYP activity is inconclusive. This commentary will discuss the relevance of such drug-biologic interactions and whether current PBPK models considering only IL-6 are sufficient. Significance Statement This commentary summarizes the current in vitro and in vivo literature regarding cytokine-mediated CYP suppression and compares the relative suppressive potential of different cytokines in reference to IL-6. It also discusses the relevance of drug-biologic interactions to therapeutic use of small molecule drugs and whether current PBPK models considering only IL-6 are sufficient to predict the extent of drug-biologic interactions.

Penetrating-peptide-mediated non-invasive Axitinib delivery for anti-neovascularisation.

The unique physiological makeup of the eye limits the use of small-molecule drugs for treating the posterior segment of the eye. Nevertheless, transmembrane-peptide-mediated non-invasive drug delivery can serve as an ideal treatment strategy, as it is capable of delivering small-molecule drugs across the membrane in the form of eye drops, thereby achieving the effective treatment of neovascularisation in the posterior cavity. In this study, we screened and compared the posterior segment distribution of two poly(ethylene glycol)-distearoylphosphatidylethanolamine carriers modified using targeting-peptides. Thereafter, a transmembrane peptide (i.e., PENE) with a greater ability of transmembrane delivery was selected for delivering the anti-vascular drug (i.e., Axitinib) to the posterior segment of the eye. Using two different mouse models with fundus neovascular diseases, the complete non-invasive delivery of Axitinib to the posterior segment of the eye was confirmed using the targeted system; the designed eye drops (i.e., PENE-nanoparticles) could achieve drug distribution to the retina and veins of the eye as well as good drug permeability for renewal. Moreover, using the eye-drop treatment, neovascularisation was substantially reduced, demonstrating the high efficacy of this drug delivery system. This study, which combines nanodrug-loading technology and the transmembrane delivery of penetrating-peptides to achieve the goal of the non-invasive delivery of small-molecule drugs through the dense blood vessels of the sclera, shows wide applicability and considerably expands the use of ocular drugs. Thus, this study is expected to help develop a more acceptable drug administration strategy for the drug treatment of the posterior segment of the eye.

Nanotechnology-Driven Cell-Based Therapies in Regenerative Medicine.

The administration of cells as therapeutic agents has emerged as a novel approach to complement the use of small molecule drugs and other biologics for the treatment of numerous conditions. Although the use of cells for structural and/or functional tissue repair and regeneration provides new avenues to address increasingly complex disease processes, it also faces numerous challenges related to efficacy, safety, and translational potential. Recent advances in nanotechnology-driven cell therapies have the potential to overcome many of these issues through precise modulation of cellular behavior. Here, we describe several approaches that illustrate the use of different nanotechnologies for the optimization of cell therapies and discuss some of the obstacles that need to be overcome to allow for the widespread implementation of nanotechnology-based cell therapies in regenerative medicine.

Population Pharmacokinetic Modeling of Inebilizumab in Subjects with Neuromyelitis Optica Spectrum Disorders, Systemic Sclerosis, or Relapsing Multiple Sclerosis.

Background and ObjectiveInebilizumab is a humanized, affinity-optimized, afucosylated immunoglobulin (Ig)-G1κ monoclonal antibody that binds to CD19, resulting in effective depletion of peripheral B cells. It is being developed to treat various autoimmune diseases, including neuromyelitis optica spectrum disorders (NMOSD), systemic sclerosis (SSc), and relapsing multiple sclerosis (MS). MethodsPharmacokinetic data from a pivotal study in adult subjects with NMOSD and two early-stage studies in subjects with SSc or relapsing MS were pooled and simultaneously analyzed using a population approach.ResultsUpon intravenous administration, the pharmacokinetics of inebilizumab were adequately described by a two-compartment model with parallel first-order and time-dependent nonlinear elimination pathways. An asymptotic nonlinear elimination suggests that inebilizumab undergoes receptor (CD19)-mediated clearance. The estimated systemic clearance (CL) of the first-order elimination pathway (0.188 L/day) and the volume of distribution (Vd) (5.52 L) were typical for therapeutic immunoglobulins. The elimination half-life was approximately 18 days. The maximum velocity (Vmax) of the nonlinear elimination pathway decreased with time, presumably due to the depletion of B cells upon inebilizumab administration. As for other therapeutic monoclonal antibodies, the CL and Vd of inebilizumab increased with body weight.ConclusionsThe presence of antidrug antibodies, status of hepatic or renal function, and use of small-molecule drugs commonly used by subjects with NMOSD had no clinically relevant impact on the pharmacokinetics of inebilizumab. The nonlinear elimination pathway at the 300 mg therapeutic dose level is not considered clinically relevant.

Targeting the Inside of Cells with Biologicals: Chemicals as a Delivery Strategy.

Delivering macromolecules into the cytosol or nucleus is possible in vitro for DNA, RNA and proteins, but translation for clinical use has been limited. Therapeutic delivery of macromolecules into cells requires overcoming substantially higher barriers compared to the use of small molecule drugs or proteins in the extracellular space. Breakthroughs like DNA delivery for approved gene therapies and RNA delivery for silencing of genes (patisiran, ONPATTRO®, Alnylam Pharmaceuticals, Cambridge, MA, USA) or for vaccination such as the RNA-based coronavirus disease 2019 (COVID-19) vaccines demonstrated the feasibility of using macromolecules inside cells for therapy. Chemical carriers are part of the reason why these novel RNA-based therapeutics possess sufficient efficacy for their clinical application. A clear advantage of synthetic chemicals as carriers for macromolecule delivery is their favourable properties with respect to production and storage compared to more bioinspired vehicles like viral vectors or more complex drugs like cellular therapies. If biologicals can be applied to intracellular targets, the druggable space is substantially broadened by circumventing the limited utility of small molecules for blocking protein–protein interactions and the limitation of protein-based drugs to the extracellular space. An in depth understanding of the macromolecular cargo types, carrier types and the cell biology of delivery is crucial for optimal application and further development of biologicals inside cells. Basic mechanistic principles of the molecular and cell biological aspects of cytosolic/nuclear delivery of macromolecules, with particular consideration of protein delivery, are reviewed here. The efficiency of macromolecule delivery and applications in research and therapy are highlighted.

Mini-Review; Deriving Avian Stem Cells by Small Molecules.

Avian embryos and related cell lines have found wide applications in basic and applied sciences. The embryonated egg is a great host for monoclonal antibodies and recombinant proteins. Avian cell lines derived from embryonated eggs have been used for the production of transgenic birds and virus inoculation in vaccine preparation. Hitherto, many efforts have been invested to develop efficient avian stem cell culture. Under the conventional conditions, there are various challenges, such as the type of feeder layers, conditioned medium, serum, and growth factors. Researchers have investigated different conditions to solve these problems. Recent studies have shown that targeted strategies using small molecule inhibitors could be used as alternatives to multi-growth factor delivery approaches. Since small molecule inhibitors were used for mammalian pluripotent stem cells (PSC), several kinds of research have examined the effect of the small molecule on self- -renewal and maintenance of avian PSC. Avian PSC can be derived from early blastodermal cells (stage X), circular primoridial germ cells (PGC; stage HH17), gonadal PGC (stage HH28), and embryonic germ cells (EGC; HH28). Previous studies have shown that the use of small molecule drugs such as PD0325901, SB431542, SC1, IDE1, Z-VAD, Blebbistatin, H-1152, and IDE1 could be an efficient method for the derivation of avian stem cells. This mini-review covers the recent development of avian stem cell culture by small molecules.

Empirical and theoretical insights into the structural effects of selenite doping in hydroxyapatite and the ensuing inhibition of osteoclasts.

The use of ions as therapeutic agents has the potential to minimize the use of small-molecule drugs and biologics for the same purpose, thus providing a potentially more economic and less adverse means of treating, ameliorating or preventing a number of diseases. Hydroxyapatite (HAp) is a solid compound capable of accommodating foreign ions with a broad range of sizes and charges and its properties can dramatically change with the incorporation of these ionic additives. While most ionic substitutes in HAp have been monatomic cations, their lesser atomic weight, higher diffusivity, chaotropy and a lesser residence time on surfaces theoretically makes them prone to exert a lesser influence on the material/cell interaction than the more kosmotropic oxyanions. Selenite ion as an anionic substitution in HAp was explored in this study for its ability to affect the short-range and the long-range crystalline symmetry and solubility as well as for its ability to affect the osteoclast activity. We combined microstructural, crystallographic and spectroscopic analyses with quantum mechanical calculations to understand the structural effects of doping HAp with selenite. Integration of selenite ions into the crystal structure of HAp elongated the crystals along the c-axis, but isotropically lowered the crystallinity. It also increased the roughness of the material in direct proportion with the content of the selenite dopant, thus having a potentially positive effect on cell adhesion and integration with the host tissue. Selenite in total acted as a crystal structure breaker, but was also able to bring about symmetry at the local and global scales within specific concentration windows, indicating a variety of often mutually antagonistic crystallographic effects that it can induce in a concentration-dependent manner. Experimental determination of the lattice strain coupled with ab initio calculations on three different forms of carbonated HAp (A-type, B-type, AB-type) demonstrated that selenite ions initially substitute carbonates in the crystal structure of carbonated HAp, before substituting phosphates at higher concentrations. The most energetically favored selenite-doped HAp is of AB-type, followed by the B-type and only then by the A-type. This order of stability was entailed by the variation in the geometry and orientation of both the selenite ion and its neighboring phosphates and/or carbonates. The incorporation of selenite in different types of carbonated HAp also caused variations of different thermodynamic parameters, including entropy, enthalpy, heat capacity, and the Gibbs free energy. Solubility of HAp accommodating 1.2wt% of selenite was 2.5 times higher than that of undoped HAp and the ensuing release of the selenite ion was directly responsible for inhibiting RAW264.7 osteoclasts. Dose-response curves demonstrated that the inhibition of osteoclasts was directly proportional to the concentration of selenite-doped HAp and to the selenite content in it. Meanwhile, selenite-doped HAp had a significantly less adverse effect on osteoblastic K7M2 and MC3T3-E1 cells than on RAW264.7 osteoclasts. The therapeutically promising osteoblast vs. osteoclast selectivity of inhibition was absent when the cells were challenged with undoped HAp, indicating that it is caused by selenite ions in HAp rather than by HAp alone. It is concluded that like three oxygens building the selenite pyramid, the coupling of (1) experimental materials science, (2) quantum mechanical modeling and (3) biological assaying is a triad from which a deeper understanding of ion-doped HAp and other biomaterials can emanate.

Effect of small molecule signaling in PepFect14 transfection.

Cell-penetrating peptides can be used to deliver oligonucleotide-based cargoes into cells. Previous studies have shown that the use of small molecule drugs could be an efficient method to increase the efficacy of delivery of oligonucleotides by cell-penetrating peptides either as targeting agents that can be used in formulation with the cell-penetrating peptide and its cargo or as cell signaling modulators that facilitates the cellular uptake of the treatment. This study presents two aims. The first aim is the identification of small molecule drugs that would induce a synergic effect on the transfection of splice correcting oligonucleotides assisted by PepFect14. The second aim is to identify the mechanisms behind the effect of small molecule drugs modulation of cell-penetrating peptide assisted transfection of oligonucleotides. Through an optimized, high-throughput luciferase assay for short oligonucleotide delivery using cell-penetrating peptides, and the simultaneous addition of a small molecule drug library, we show that three small molecule drugs (MPEP, VU0357121 and Ciproxifan) induced an increase in the transfection efficacy of PepFect14 in complex with a short single-stranded oligonucleotide in HeLa pLuc705 cells. These three drugs are described in the literature to be highly specific for their respective target receptors. However, none of those receptors are expressed in our cell line, indicating a yet non-described pathway of action for these small molecules. We show that the indicated small molecules, without interfering with the particles formed by PepFect14 and the oligonucleotide, interfere via still unidentified interactions in cell signaling, leading to an up-regulation of endocytosis and a higher efficacy in the delivery of short splice correcting oligonucleotides in complex with PepFect14.

Mapping the Interactions of HBV cccDNA with Host Factors.

Hepatitis B virus (HBV) infection is a major health problem affecting about 300 million people globally. Although successful administration of a prophylactic vaccine has reduced new infections, a cure for chronic hepatitis B (CHB) is still unavailable. Current anti-HBV therapies slow down disease progression but are not curative as they cannot eliminate or permanently silence HBV covalently closed circular DNA (cccDNA). The cccDNA minichromosome persists in the nuclei of infected hepatocytes where it forms the template for all viral transcription. Interactions between host factors and cccDNA are crucial for its formation, stability, and transcriptional activity. Here, we summarize the reported interactions between HBV cccDNA and various host factors and their implications on HBV replication. While the virus hijacks certain cellular processes to complete its life cycle, there are also host factors that restrict HBV infection. Therefore, we review both positive and negative regulation of HBV cccDNA by host factors and the use of small molecule drugs or sequence-specific nucleases to target these interactions or cccDNA directly. We also discuss several reporter-based surrogate systems that mimic cccDNA biology which can be used for drug library screening of cccDNA-targeting compounds as well as identification of cccDNA-related targets.

Targeted Tumor Therapy Remixed-An Update on the Use of Small-Molecule Drugs in Combination Therapies.

Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.

Microbiota and Neurological Disorders: A Gut Feeling.

In the past century, noncommunicable diseases have surpassed infectious diseases as the principal cause of sickness and death, worldwide. Trillions of commensal microbes live in and on our body, and constitute the human microbiome. The vast majority of these microorganisms are maternally derived and live in the gut, where they perform functions essential to our health and survival, including: digesting food, activating certain drugs, producing short-chain fatty acids (which help to modulate gene expression by inhibiting the deacetylation of histone proteins), generating anti-inflammatory substances, and playing a fundamental role in the induction, training, and function of our immune system. Among the many roles the microbiome ultimately plays, it mitigates against untoward effects from our exposure to the environment by forming a biotic shield between us and the outside world. The importance of physical activity coupled with a balanced and healthy diet in the maintenance of our well-being has been recognized since antiquity. However, it is only recently that characterization of the host–microbiome intermetabolic and crosstalk pathways has come to the forefront in studying therapeutic design. As reviewed in this report, synthetic biology shows potential in developing microorganisms for correcting pathogenic dysbiosis (gut microbiota–host maladaptation), although this has yet to be proven. However, the development and use of small molecule drugs have a long and successful history in the clinic, with small molecule histone deacetylase inhibitors representing one relevant example already approved to treat cancer and other disorders. Moreover, preclinical research suggests that epigenetic treatment of neurological conditions holds significant promise. With the mouth being an extension of the digestive tract, it presents a readily accessible diagnostic site for the early detection of potential unhealthy pathogens resident in the gut. Taken together, the data outlined herein provide an encouraging roadmap toward important new medicines and companion diagnostic platforms in a wide range of therapeutic indications.

Self-Reactive CFTR T Cells in Humans: Implications for Gene Therapy

Cystic fibrosis (CF) is one of the most common autosomal recessive lethal disorders affecting white populations of northern European ancestry. To date there is no cure for CF. Life-long treatments for CF are being developed and include gene therapy and the use of small-molecule drugs designed to target specific cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. Irrespective of the type of molecular therapy for CF, which may include gene replacement, exon skipping, nonsense suppression, or molecular correctors, because all of these modulate gene expression there is an inherent risk of activation of T cells against the wild-type version of CFTR. Here we report the validation of the human interferon-γ enzyme-linked immunospot assay and its application for the analysis of CFTR-specific T cell responses in patients with CF and in non-CF subjects. We found non-CF subjects with low levels of self-reactive CFTR-specific T cells in the United States and several patients with CF with low to high levels of self-reactive CFTR-specific T cells in both the United States and the United Kingdom.

IPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

The revolutionary induced pluripotent stem cell (iPSC) technology provides a new path for cell replacement therapies and drug screening. Patient-specific iPSCs and subsequent differentiated cells manifesting disease phenotypes will finally position human disease pathology at the core of drug discovery. Cells used to test the toxic effects of drugs can also be generated from normal iPSCs and provide a much more accurate and cost-effective system than many animal models. Here, we highlight the recent progress in iPSC-based cell therapy, disease modeling and drug evaluations. In addition, we discuss the use of small molecule drugs to improve the generation of iPSCs and understand the reprogramming mechanism. It is foreseeable that the interplay between iPSC technology and small molecule compounds will push forward the applications of iPSC-based therapy and screening systems in the real world and eventually revolutionize the methods used to treat diseases.

Synergistic anti-cancer effects via co-delivery of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) and doxorubicin using micellar nanoparticles

The use of small molecule drugs in cancer chemotherapy has mostly been limited by dose-dependent toxicity and development of drug resistance resulting from repeated administrations. To overcome such problems, efforts have been made to develop drug delivery systems that can bear multiple therapeutic agents in one system. The purpose of this study is to deliver human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) and doxorubicin (Dox, an anti-cancer drug) with micellar nanoparticles self-assembled from a biodegradable cationic copolymer P(MDS-co-CES) to achieve synergistic cytotoxic effects in cancer cells. Exogenously expressed TRAIL using recombinant methods shows great potential in cancer therapy as it induces cell death selectively in cancer cells with limited toxicity to normal tissues. Dox-loaded nanoparticles and TRAIL formed stable nanocomplexes with a size of ∼ 225 nm and zeta potential of ∼ 70 mV. Effects of nanocomplexes on both wild type and TRAIL-resistant SW480 colorectal carcinoma cells were investigated. The assemblies of Dox and TRAIL with P(MDS-co-CES) nanoparticles were efficiently delivered to cancer cells. Receptor-blocking studies showed that the nanocomplexes entered cells via death receptor-mediated endocytosis. Synergism in cell death induction was analysed by the isobologram method to study drug interactions. Cytotoxicity of the nanocomplexes to non-cancerous cells was significantly lower than cancerous cells. Anti-proliferative effects of nanocomplexes were retained in remaining cancer cells in long-term cultures after treatment with the nanocomplexes. In summary, this Dox and TRAIL co-delivery system can be a promising candidate for cancer treatment.