Small-molecule Chemical Drugs Research Articles

Study on the molecular interactions between givosiran and theophylline by surface-enhanced Raman spectroscopy, biolayer interferometry, and visible/fluorescence spectroscopy

Givosiran is a small-interfering ribonucleic acid (siRNA) drug used to treat acute hepatic porphyria. As an exogenous double-stranded RNA, givosiran has a specific spatial conformation. When they coexist, givosiran and small-molecule drugs may interact through non-covalent bonds, which may affect their efficacies. This study aimed to evaluate the molecular interaction between givosiran and three structurally-related small-molecule drugs. We combined surface-enhanced Raman spectroscopy, biolayer interferometry, and visible/fluorescence spectroscopy with a methylene blue probe to study the molecular interaction between givosiran and theophylline, caffeine, and theobromine. Molecular interactions were observed only between theophylline and givosiran, with an affinity constant (KD) of 64.2 μM. The main binding forces were hydrogen bonds and van der Waals forces, and the equilibrium binding constant (KA) was 1.855 × 104 L·mol−1. This study focused on the 5 W (Whether, Where, Why, hoW about the tendency, hoW strong) issues of the molecular interaction between givosiran and small-molecule chemical drugs. Our findings contradict the previous perception that the probability of drug–drug interactions (DDI) between nucleic acid and small-molecular drugs is low. Our study illustrates that a combination of direct and indirect analytical methods will pave a new way for future siRNA-related unknown interactions studies.

Significant downregulation of Alzheimer's amyloid-β levels enabled by engineered DNA nanomaterials

Although there are no effective therapies to block or reverse Alzheimer's disease (AD) progression at present, a promising therapeutic strategy is to reduce levels of amyloid-β (Aβ) proteins, which drive the formation of amyloid plaque, a primary hallmark in AD brains. Herein, we report that amphiphilic lipid-DNA molecules (LD) were designed by incorporating a long alkyl chain into the nucleotide base. It significantly down-regulated Alzheimer's Aβ levels in vivo and in vitro. In contrast to small-molecule chemical drugs and antibody therapies, the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier (BBB) and accumulate in the brain, increasing the therapeutic effects. Notably, lipid-DNA downregulated the levels of Aβ peptides significantly in vitro. AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement, which was associated with brain engagement of LD and reduced Aβ levels. Thus, the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides. This work might provide a promising DNA engineering strategy for AD treatment.

Personalized Drug Therapy: Innovative Concept Guided With Proteoformics

Personalized medicine can reduce adverse effects, enhance drug efficacy, and optimize treatment outcomes, which represents the essence of personalized medicine in the pharmacy field. Protein drugs are crucial in the field of personalized drug therapy and are currently the mainstay, which possess higher target specificity and biological activity than small-molecule chemical drugs, making them efficient in regulating disease-related biological processes, and have significant potential in the development of personalized drugs. Currently, protein drugs are designed and developed for specific protein targets based on patient-specific protein data. However, due to the rapid development of two-dimensional gel electrophoresis and mass spectrometry, it is now widely recognized that a canonical protein actually includes multiple proteoforms, and the differences between these proteoforms will result in varying responses to drugs. The variation in the effects of different proteoforms can be significant and the impact can even alter the intended benefit of a drug, potentially making it harmful instead of lifesaving. As a result, we propose that protein drugs should shift from being targeted through the lens of protein (proteomics) to being targeted through the lens of proteoform (proteoformics). This will enable the development of personalized protein drugs that are better equipped to meet patients' specific needs and disease characteristics. With further development in the field of proteoformics, individualized drug therapy, especially personalized protein drugs aimed at proteoforms as a drug target, will improve the understanding of disease mechanisms, discovery of new drug targets and signaling pathways, provide a theoretical basis for the development of new drugs, aid doctors in conducting health risk assessments and making more cost-effective targeted prevention strategies conducted by artificial intelligence/machine learning, promote technological innovation, and provide more convenient treatment tailored to individualized patient profile, which will benefit the affected individuals and society at large.

A universal powder-laden crosslinked chitosan microneedle patch for high-dose controllable drug delivery

In this study, we constructed a novel powder-laden core–shell crosslinked chitosan microneedle patch for high-dose and controllable delivery of various drugs, including both macromolecular biological drugs and small-molecule chemical drugs. Direct loading of drug powders greatly improved drug loading capacity and minimized degradation. The results of the in vitro drug release study suggested that the release behaviors of the most tested drugs (both macromolecular drugs and small-molecule drugs) can be tuned by adjusting the crosslink density of the microneedle shell to achieve either rapid or sustained release of the loaded drug. The in vivo hypoglycemic efficacy test in streptozotocin-induced diabetic mice further proved that the onset and duration of the insulin-laden patch can be customized by adjusting the crosslink density. Furthermore, a combination of microneedle patches with different crosslink densities not only rapidly reduced blood glucose levels to normoglycemic levels (within 1 h) but also maintained normoglycemia for up to 36 h. The insulin loaded in the patch also showed good stability during storage at 40 °C for 6 months. Our results suggest that this powder-laden patch represents a strong candidate for addressing the multiple challenges in the preparation and application of polymeric microneedles and shows promise in clinical applications.

What is the role of current mass spectrometry in pharmaceutical analysis?

The role of mass spectrometry (MS) has become more important in most application domains in recent years. Pharmaceutical analysis is specific due to its stringent regulation procedures, the need for good laboratory/manufacturing practices, and a large number of routine quality control analyses to be carried out. The role of MS is, therefore, very different throughout the whole drug development cycle. While it dominates within the drug discovery and development phase, in routine quality control, the role of MS is minor and indispensable only for selected applications. Moreover, its role is very different in the case of analysis of small molecule pharmaceuticals and biopharmaceuticals. Our review explains the role of current MS in the analysis of both small-molecule chemical drugs and biopharmaceuticals. Important features of MS-based technologies being implemented, method requirements, and related challenges are discussed. The differences in analytical procedures for small molecule pharmaceuticals and biopharmaceuticals are pointed out. While a single method or a small set of methods is usually sufficient for quality control in the case of small molecule pharmaceuticals and MS is often not indispensable, a large panel of methods including extensive use of MS must be used for quality control of biopharmaceuticals. Finally, expected development and future trends are outlined.

Metformin: A promising drug for human cancers.

Small-molecule chemical drugs are of great significance for tumor-targeted and individualized therapies. However, the development of new small-molecule drugs, from basic experimental research and clinical trials to final application in clinical practice, is a long process that has a high cost. It takes at least 5 years for most drugs to be developed in the laboratory to prove their effectiveness and safety. Compared with the development of new drugs, repurposing traditional non-tumor drugs can be a shortcut. Metformin is a good model for a new use of an old drug. In recent years, the antitumor efficacy of metformin has attracted much attention. Epidemiological data and in vivo, and in vitro experiments have shown that metformin can reduce the incidence of cancer in patients with diabetes and has a strong antagonistic effect on metabolism-related tumors. Recent studies have shown that metformin can induce autophagy in esophageal cancer cells, mainly by inhibiting inflammatory signaling pathways. In recent years, studies have shown that the antitumor functions and mechanisms of metformin are multifaceted. The present study aims to review the application of metformin in tumor prevention and treatment.

Adverse Drug Reactions and Toxicity of the Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.

The market for large molecule biologic drugs has grown rapidly, including antisense oligonucleotide (ASO) drugs. ASO drugs work as single-stranded synthetic oligonucleotides that reduce production or alter functions of disease-causing proteins through various mechanisms, such as mRNA degradation, exon skipping, and ASO-protein interactions. Since the first ASO drug, fomivirsen, was approved in 1998, the U.S. Food and Drug Administration (FDA) has approved 10 ASO drugs to date. Although ASO drugs are efficacious in treating some diseases that are untargetable by small-molecule chemical drugs, concerns on adverse drug reactions (ADRs) and toxicity cannot be ignored. Illustrative of this, mipomersen was recently taken off the market due to its hepatotoxicity risk. This paper reviews ADRs and toxicity from FDA drug labeling, preclinical studies, clinical trials, and postmarketing real-world studies on the 10 FDA-approved ASO drugs, including fomivirsen and pegaptanib, mipomersen, nusinersen, inotersen, defibrotide, eteplirsen, golodirsen, viltolarsen, and casimersen. Unique and common ADRs and toxicity for each ASO drug are summarized here. The risk of developing hepatotoxicity, kidney toxicity, and hypersensitivity reactions co-exists for multiple ASO drugs. Special precautions need to be in place when certain ASO drugs are administrated. Further discussion is extended on studying the mechanisms of ADRs and toxicity of these drugs, evaluating the existing physiologic and pathologic states of patients, optimizing the dose and route of administration, and formulating personalized treatment plans to improve the clinical utility of FDA-approved ASO drugs and discovery and development of new ASO drugs with reduced ADRs. SIGNIFICANCE STATEMENT: The current review provides a comprehensive analysis of unique and common ADRs and the toxicity of FDA-approved ASO drugs. The information can help better manage the risk of severe hepatotoxicity, kidney toxicity, and hypersensitivity reactions in the usage of currently approved ASO drugs and the discovery and development of new and safer ASO drugs.

The Trend of Targeted Therapies in Chinese Patients With Ankylosing Spondylitis: Results From a Real-Life Survey.

Introduction : Targeted medication, including mostly biologics and small-molecule chemical drugs, is an important therapy for ankylosing spondylitis (AS). There are still limited data on the preference of different targeted drugs in Chinese AS patients. Methods : A questionnaire-based cross-sectional study was performed on AS patients from six hospitals in three provinces in South China. Anti-rheumatic diseases’ medication history includes the recent and previous usage of biologics or Janus kinase inhibitors (JAKi) in the last complete course of treatment, disease severity, and reasons for targeted-treatment change or preference. Results : 354 of 366 participants responded to the online survey. The participants’ median age was 32 years, with a median of 7.3 years of disease duration; 79.7% were male. 63.6% of them were in the course of biologics or JAKi. Generic ETN is the most widely used and willing-to-use biologic though the proportion of its usage shrunk in the present compared with the past. The choice of original-branded ADA demonstrated an increase in usage. The preference of secukinumab and tofacitinib depicted a quick ascending trend. Conclusion : TNF-α inhibitors (TNFi) are still the most popular targeted medication for AS in China. Their price influences patients’ preferences mostly. The doctor’s recommendation is also part of the equation. Rheumatologists should pay more attention to patients’ education to formulate targeted therapeutic plans.

Antigen Design for Successful Isolation of Highly Challenging Therapeutic Anti-GPCR Antibodies.

G-protein-coupled receptors (GPCR) transmit extracellular signals into cells to regulate a variety of cellular functions and are closely related to the homeostasis of the human body and the progression of various types of diseases. Great attention has been paid to GPCRs as excellent drug targets, and there are many commercially available small-molecule chemical drugs against GPCRs. Despite this, the development of therapeutic anti-GPCR antibodies has been delayed and is challenging due to the difficulty in preparing active forms of GPCR antigens, resulting from their low cellular expression and complex structures. Here, we focus on anti-GPCR antibodies that have been approved or are subject to clinical trials and present various technologies to prepare active GPCR antigens that enable the isolation of therapeutic antibodies to proceed toward clinical validation.

Binary blended co-delivery nanoparticles with the characteristics of precise pH-responsive acting on tumor microenvironment.

Although combined chemotherapy had achieved the ideal efficacy in clinical anti-cancer therapeutic, the issues that need to be addressed are non-targeting and toxic-side effects of small molecule chemical drug (SMCD). In this study, we designed and prepared a novel binary blended co-delivered nanoparticles (BBCD NPs) with pH-responsive feature on tumor microenvironment. The BBCD NPs consists of two kind of drug-loaded NPs, in one of which carboxymethyl chitosan (CMC) and Poly (lactic-co-glycolic acid) (PLGA) were chosen as delivery carrier to load anti-cancer drug vincristine (VCR), named CMC-PLGA-VCR NPs (or CPNPVCR); and in the other of which methoxy poly(ethylene glycol)-poly(β-amino ester) (mPEG-PAE) were chosen as delivery carrier to load anti-fibrotic drug pirfenidone (PFD), named mPEG-PAE-PFD NPs (or PPNPPFD). Then, the two types of NPs (CPNPVCR and PPNPPFD) were physically mixed in mass ratios to form BBCD NPs, which was named CPNPVCR&PPNPPFD. CPNPVCR&PPNPPFD had good encapsulation efficiency and loading capacity, and the particle size distribution was uniform. In cytotoxicity experiments and non-contact co-culture studies in vitro, the model drugs loaded in CPNPVCR&PPNPPFD could respectively target cancer cell and cancer associated fibroblast (CAF) owing to the precise pH-sensitive drug release in the pharmacological targets and show stronger synergism than that of the combined treatment of two free drugs. As a modularity and assemble ability feature in design, BBCD NPs would have the advantages on the terms of concise on preparation process, controllable on quality standard, stable in natural environment storage. The research results can provide scientific evidence for the further development of a novel drug co-delivery system with multi-type cell targets.

Crystal Transformation of β-CD-MOF Facilitates Loading of Dimercaptosuccinic Acid.

The β-cyclodextrin-metal-organic framework (β-CD-MOF), a potential drug delivery carrier, presents a densely packed laminated crystal structure (CCDC number 1041782) that prevents drug from entering inside the molecular voids in most CD units. In this paper, it was demonstrated that dimercaptosuccinic acid (DMSA), an instable small molecule chemical drug, was successfully loaded in β-CD-MOF with a high molar ratio of 1:1.35 (β-CD-MOF:DMSA) determined by high-performance liquid chromatography. The drug loading mechanism of β-CD-MOF/DMSA was supported by a series of experimental characterizations and molecular simulations. The morphology observations revealed that crystalline particles of β-CD-MOF transformed to reticular microstructure after drug loading evidenced by powder X-ray diffraction (PXRD), scanning electron microscope (SEM), synchrotron radiation Fourier transform infrared spectroscopy (SR-FTIR), and etc. It is of interest to note that the stability of DMSA was well improved by β-CD-MOF, but decreased by γ-CD-MOF, indicating different protective capacities between the two types of CD-MOFs. Thus, it is hypothesized that the transformation from laminated molecular arrangement of β-CD-MOF to reticular microstructure leads to an enhanced drug-loading capability for delivery of specific drugs.

Derivation of Inhibitory Peptides to Target the Cardiac Troponin C–I Interaction as Potential Therapeutics for Heart Failure

The Ca2+-sensitive cardiac troponin (cTn) is a hetero-trimer complex consisting of three subunits cTnC, cTnI, and cTnT, which has been recognized as an important biomarker and a potential target of cardiovascular diseases. Previously, several small-molecule agents such as levosimendan and pimobendan have been successfully developed to target this protein for the treatment of heart failure. Here, instead of small-molecule chemical drugs, we purposed rational derivation of self-inhibitory peptides as potential biologic disruptors of cTnC–cTnI interaction from the interaction complex interface. In the procedure, the crystal structure of cTn trimer was examined in detail using bioinformatics approach, from which a peptide-mediated interaction between the N-terminal domain of cTnC and the switch region of cTnI was identified. The switch is a 19-mer peptide segment Swt that contains a structured helical core capped by a short N-terminal tripeptide and a disordered C-terminal tail. Structural and energetic analysis revealed that the Swt peptide binds independently to cTnC N-terminal domain, which can be stripped from the intact cTnI subunit to interact effectively with cTnC. Further investigations found that truncation of two N-terminal residues and five C-terminal residues of the full-length Swt peptide, resulting in a shortened version namely Swt-ΔN2ΔC5 peptide, would not cause substantial loss in its binding potency to cTnC. The computational finding was then confirmed by using fluorescence-based affinity assays; the Swt and Swt-ΔN2ΔC5 peptides was experimentally measured to have a moderately high affinity to the recombinant protein of human cTnC N-terminal domain with K d values at micromolar level. The Swt and Swt-ΔN2ΔC5 are considered as inhibitory peptides that can be further optimized and modified to obtain high-affinity disruptors of cTnI–cTnC interaction.

Erythropoietin.

Total hemoglobin (Hb) mass is an important determinant of aerobic power. The glycoprotein erythropoietin (Epo) promotes the production of red blood cells (RBCs). The present article reviews the regulation of erythropoiesis and ways of its manipulation. The various Epos, e.g. recombinant human (rh)Epo and (epoetin), and their long-acting analogues can be misused by cheating athletes, but the drugs are detectable by chemical tests, because their glycan isoform structures differ from those of endogenous Epo. Still, anti-doping control has become more difficult, since additional erythropoiesis-stimulating agents have become available (Epo mimetics, activin inhibitors, and small-molecule chemical drugs activating EPO expression). A major problem is created by hypoxia-inducible factor (HIF) stabilizers (e.g. α-ketoglutarate competitors and Co2+ salt) which activate HIFs and thus increase EPO expression. Direct EPO transfer is theoretically also possible but medically little advanced. To overcome weaknesses of direct testing of biological fluids, the World Anti-Doping Agency has implemented the Athlete Biological Passport for continuous monitoring of RBC parameters of athletes. Blood doping is assumed when distinct parameters (blood Hb concentration and reticulocytes) change in a nonphysiological way.

Sandoz v. Amgen: Why the Biologics Price Competition and Innovation Act of 2009 Allows Biosimilar Makers to Pursue Pre-Application Declaratory Judgment Actions and Will Enhance Competition

The generic drug industry is shifting towards biosimilars. In the coming years, first-generation blockbuster biologic drugs will come off patent protection. However, unlike the small-molecule chemical drug market where exact generic copies can be produced, the complexity of large-molecule biologic drugs makes exact replicates impossible. As a result, biologic copies aim to be as similar as possible to their blockbuster counterparts – thus, the name: biosimilars. The Biologics Price Competition and Innovation Act of 2009 (BPCIA) regulates biosimilar approval.Submarine patents threaten the development of biosimilars. These types of patents are a product of manipulative continuation practices by the applicant, and can result in patent issuance more than a decade after the filing date. Submarine patents are meant to surprise an industry and preclude competition. While some believe submarine patents are a thing of the past, a pending case before the Federal Circuit shows they are not. In Sandoz v. Amgen, the Federal Circuit’s interpretation of the BPCIA will determine what litigation strategies are available to biosimilar makers to combat submarine patents. This is the first case to arise in the biosimilar industry. The issue is one of pure statutory interpretation: does the BPCIA bar a biosimilar maker from filing a declaratory judgment (DJ) action before submitting an application for approval.This article argues that the BPCIA does not preclude pre-application DJ actions. In addition, the article posits that pre-application DJ actions are an important tool in the fight against submarine patents and will enhance competition. The biosimilar industry is fast approaching and the legal community must take notice. This article seeks to further that conversation.

‘Similar biologics’ approved and marketed in India

There have been established guidelines for approving generic versions of small molecule chemical drugs in India for some time already. However, no specific guidelines for 'similar biologics', as the Indian regulatory authorities call these products, have existed in India until recently. This has been the case despite

Combinatorial selection and delivery of thioaptamers

Oligonucleotide-based agents are emerging as potential therapeutic agents that can be attractive alternatives for the small-molecule chemical drugs. Monothiophosphate-backbone-modified DNA aptamers (thioaptamers) that specifically and tightly bind to the RNase H domain of the HIV RT (reverse transcriptase) have been isolated from nucleic acid libraries using combinatorial selection methods. The selected thioaptamer inhibited RNase H activity of the HIV RT in in vitro studies. In cell cultures, the transfected thioaptamer markedly reduced HIV production in a dose-dependent manner. Gel electrophoretic mobility-shift assays and NMR spectroscopy showed that the selected thioaptamer binds to the isolated RNase H domain, but did not bind to a structurally similar RNase H from Escherichia coli. In cell cultures, the transfected thioaptamer showed a dose-dependent inhibition of HIV replication, with a maximal inhibition of 83%. Using various liposome-delivery agents, the DNA thioaptamer was transfected into HIV-infected astrocytoma adherent cells with greater than 70% efficiency.