Future Pharmacology

The main proteinase (Mpro), or 3CLpro, is a critical enzyme in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lifecycle and is responsible for breaking down and releasing vital functional viral proteins crucial for virus development and transmission. As a catalytically active dimer, its dimerization interface has become an attractive target for antiviral drug development. Recent research has extensively investigated the enzymatic activity of Mpro, focusing on its role in regulating the coronavirus replication complex and its significance in virus maturation and infectivity. Computational investigations have identified four druggable pockets, suggesting potential allosteric sites beyond the substrate-binding region. Empirical validation through site-directed alanine mutagenesis has targeted residues in both the active and allosteric regions and corroborated these predictions. Structural studies of drug target proteins can inform therapeutic approaches, with metadynamics simulations shedding light on the role of H163 in regulating Mpro function and providing insights into its dynamic equilibrium to the wild-type enzyme. Despite the efficacy of vaccines and drugs in mitigating SARS-CoV-2 spread, its ongoing viral evolution, selective pressures, and continued transmission pose challenges, potentially leading to resistant mutations. Phylogenetic analyses have indicated the existence of several resistant variations predating drug introduction to the human population, emphasizing the likelihood of drug spread. Hydrogen/deuterium-exchange mass spectrometry reveals the structural influence of the mutation. At the same time, clinical trials on 3CLPro inhibitors underscore the clinical significance of reduced enzymatic activity and offer avenues for future therapeutic exploration. Understanding the implications of 3CLPro mutations holds promise for shaping forthcoming therapeutic strategies against COVID-19. This review delves into factors influencing mutation rates and identifies areas warranting further investigation, providing a comprehensive overview of Mpro mutations, categorization, and terminology. Moreover, we examine their associations with clinical outcomes, illness severity, unresolved issues, and future research prospects, including their impact on vaccine efficacy and potential therapeutic targeting. Full article

Background. Peptidergic GPCR systems are broadly distributed in the human body and regulate numerous physiological processes by activating complex networks of intracellular biochemical events responsible for cell regulation and survival. Excessive stimulation, ill-function, or blockade of GPCRs produces cell disturbances that may cause disease should compensatory mechanisms not suffice. Methods and Results. Revision of updated experimental research provided an evident relationship associating peptidergic GPCR malfunction with tumor formation and maintenance resulting from uncontrolled cell proliferation and migration, colonization, inhibition of apoptosis or altered metabolism, and increased angiogenesis in tumoral tissues. Conclusion. Determination of the implication of GPCR peptide signaling in specific neoplasia is crucial to designing tailored pharmacological treatments to counteract or dismantle the origin of the signaling circuitry causing cellular disruption. In some cases, particular ligands for these receptors may serve as concomitant treatments to aid other pharmacological or physical approaches to eradicate neoplasias. Full article

Background/Objectives: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by cutaneous and visceral fibrosis, vascular alterations, and a persistent inflammatory response. Despite advances in understanding the pathogenic mechanisms underlying SSc, current therapeutic options remain limited. Chlorogenic acid (CGA) is a polyphenol widely distributed in plants and has shown antioxidant, anti-inflammatory, and antifibrotic properties. However, its therapeutic potential in SSc has not been investigated yet. Methods: A model of SSc was established by administering bleomycin (BLM) at 100 U/kg to CD1 mice via an osmotic minipump. After fourteen days of BLM administration, CGA (60 mg/kg) was intragastric administered on consecutive days until day 20. On day 21, all mice were sacrificed. The effect of CGA was histologically evaluated by hematoxylin and eosin and Masson’s trichrome staining. Results: CGA treatment significantly attenuated dermal fibrosis in the BLM-induced mice model of SSc by reducing histopathological damage, including increased dermal thickness, inflammation, collagen deposition, and SSc-associated pulmonary fibrosis. Conclusions: The evidence shows that CGA attenuates BLM-induced SSc in a mice model and strongly suggests that CGA may be a promising compound for the treatment of SSc. Full article

Drug-coated balloons (DCBs) have emerged as an increasingly valuable option for the treatment of coronary artery disease (CAD). Percutaneous coronary intervention (PCI) with DCBs enables the localized delivery of antiproliferative drugs directly to the target coronary lesion, avoiding the need for permanent scaffold implantation. Historically, paclitaxel-coated balloons (PCBs) have been the most used device in this context. Paclitaxel interferes with intracellular microtubule function, leading to cell cycle arrest. However, its cytotoxicity at a higher dosage and narrow therapeutic range has raised some safety concerns. To address these issues, sirolimus-coated balloons (SCBs) have been introduced as an alternative. Sirolimus acts as a cytostatic agent with potent anti-inflammatory and antiproliferative properties and is characterized by a wider therapeutic range, potentially offering a safer profile. Several experimental and clinical studies comparing the safety and efficacy of PCBs versus SCBs have yielded mixed results. Recently, a novel DCB (SirPlux Duo), which simultaneously releases both paclitaxel and sirolimus, has been tested in a porcine coronary model with promising results. In this review, we will elucidate the mechanisms of action of paclitaxel and sirolimus, examine contemporary preclinical and clinical evidence comparing PCB and SCB angioplasty, and discuss novel devices that may enhance the safety and efficacy of PCI with DCBs. Full article

Metallodrugs represent a critical area of medicinal chemistry with the potential to address a wide range of diseases. Their design requires a multidisciplinary approach, combining principles of inorganic chemistry, pharmacology, and molecular biology to create effective and safe therapeutic agents. Vanadium, the element of the fifth group of the first transition series (3d metals), has been already detected as a crucial species in the biological action of some enzymes, e.g., nitrogenases and chloroperoxidase; furthermore, vanadium-based compounds have recently been described as physiologically stable with therapeutic behavior, e.g., having anticancer, antidiabetic (insulin-mimicking), antiprotozoal, antibacterial, antiviral, and inhibition of neurodegenerative disease properties. Since the binding of metallodrugs to serum albumin influences the distribution, stability, toxicity (intended and off-target interactions), and overall pharmacological properties, the biophysical characterization between serum albumin and vanadium-based compounds is one of the hot topics in pharmacology. Overall, since vanadium complexes offer new possibilities for the design of novel metallodrugs, this review summarized some up-to-date biological and medicinal aspects, highlighting proteins as the main targets for the inorganic complexes based on this transition metal. Full article

Background: Croton grewioides Baill., a species native to the Caatinga, popularly known as canela de cunhã, is used in traditional medicine to treat gastrointestinal diseases such as diarrhea, gastritis and stomach ulcers. The combination of essential oils with antibiotics reveals several beneficial effects associated with the increased efficacy of these drugs against pathogenic agents. Through this perspective, this study aimed to identify the chemical composition of the essential oil of C. grewioides (OECG) and evaluate its antibacterial and antibiotic-modifying activities against standard and multiresistant bacteria. Methods: To analyze the compounds present in the oil, the techniques of gas chromatography coupled with mass spectrometry (GC/MS) and gas chromatography with a flame ionization detector (GC/FID) were used. In the bacteriological tests, the Minimum Inhibitory Concentration (MIC) was obtained by the broth microdilution technique. The modulating effect of the essential oil was determined by calculating the subinhibitory concentration, followed by a serial microdilution of the antibiotics. The MIC reduction factor (CRF) was calculated, and its data were expressed as a percentage. Results: The analysis of the chemical composition identified the presence of the major compound estragole with a relative abundance of 50.34%. The MIC values obtained demonstrated efficacy in K. pneumoniae isolated from urine with MIC values of 512 µg/mL. OECG potentiated the effects of all antibiotics tested on the strains S. aureus ATCC 29213, K. pneumoniae Carbapnemase, E. coli ATCC 25922 and S. aureus ATCC 29213 with their CRF of 97.65%, 99.80%, 99.85% and 99.88%, respectively. Conclusions: Thus, the essential oil of C. grewioides presents synergistic effects when combined with the antibiotics tested, in addition to acting in the fight against bacterial resistance to antibiotics. Full article

The high-risk Human Papillomavirus (HR-HPV) is the causal agent of different human cancers such as cervical, vulvar, and oropharynx cancer. This is because persistent HR-HPV infection alters several cellular processes involved in cell proliferation, apoptosis, immune evasion, genomic instability, and cellular transformation. The above is mainly due to the expression of early expression proteins of HR-HPV, which interact and alter these processes. HR-HPV proteins have even been shown to regulate redox state and mitochondrial metabolism, which has been suggested as a risk factor for cancer development. Redox state refers to a balance between reactive oxygen species (ROS) and antioxidants. Although ROS regulates cell signaling, high levels of ROS generate oxidative stress (OS). OS promotes damage to DNA, proteins, carbohydrates, and lipids, which causes mutation accumulation and genome instability associated with cancer development. Thus, OS has been associated with the establishment and development of different types of cancer and has recently been proposed as a cofactor in HR-HPV-associated cancers. However, OS also induces cell death, which can be used as a target for different molecules, such as phytochemicals. Furthermore, phytochemicals target HPV oncoproteins E6 and E7, causing their degradation. Because phytochemicals could induce OS and target HPV oncoproteins, we hypothesize that these compounds induce cell death in HPV-associated cancers. Since the redox state is crucial in developing, establishing, and clearing HR-HPV-associated cancer, this review focuses on evidence for using phytochemicals as therapeutic agents that target HPV proteins and the redox state to induce the elimination of HPV-related cancers. Full article

Acute lung injury (ALI) is induced by pneumonia, sepsis and other conditions. The disease characteristics include severe lung inflammation, in which various cells, such as epithelial cells, macrophages, and neutrophils, play a pivotal role. Corticosteroids and antibiotics are used to treat ALI; however, they may have side effects. Cumulative data confirm that traditional herbal medicines exert therapeutic effects against endotoxin-induced inflammatory responses in both in vitro and in vivo ALI studies. This review briefly describes the anti-ALI effects of medicinal herbal extracts (MHEs) and their molecular mechanisms, especially focusing on Toll-like receptor 4/nuclear factor kappa B cell pathways, with a brief summary of in vitro and in vivo ALI experimental models. Thus, the present review highlights the excellent potential of MHEs for ALI therapy and prevention and may also be useful for the establishment of in vitro and in vivo ALI models. Full article

Background: 4-MDMB-BUTINACA, a next-generation synthetic cannabinoid, presents significant public health and forensic challenges due to its evolving nature and potential toxicity. Methods: This study evaluates the subacute toxic effects and pharmacokinetics of 4−Fluoro MDMB−BUTINACA (4F-MDMB-BUTINACA) in adult male albino rats, administered orally for seven days at doses of 1 mg/kg, 5 mg/kg, and 15 mg/kg. The hematological, biochemical, and histopathological parameters were assessed and compared to controls. Results: The pharmacokinetics were determined using GC–MS/MS with a positive chemical ionization and granisetron as an internal standard. A histological analysis revealed inflammatory cell aggregation, congestion, hemorrhage, edema, and fibrosis in various tissues, with renal examinations showing tubule degradation, glomerular atrophy, Bowman’s space expansion, edema, and hemorrhage. The liver exhibited cellular infiltration, while cardiac muscle fibers showed myocardial fiber degradation and inflammatory cell aggregation. Biochemical assays indicated significant alterations (p < 0.05) in the serum levels of AST, ALT, ALP, GGT, total protein, albumin, triglycerides, urea, MCHC, MCV, RDW, platelets, neutrophils, eosinophils, and basophils compared to the controls. Conclusions: The validated bioanalytical method revealed rapid absorption of 4F-MDMB-BUTINACA, with a plasma half-life of 2.371 h, a volume of distribution of 2272.85 L, and a plasma clearance rate of 664.241 L/h. In conclusion, 4F-MDMB-BUTINACA is a highly toxic synthetic cannabinoid, particularly affecting the liver, kidneys, and heart. Full article

Ovarian cancer (OC) ranks as the fifth most common cancer among women in the United States and globally, posing a significant health threat. Reactive oxygen species (ROS) have emerged as critical factors in the pathophysiology of this malignancy. ROS, characterized by their instability due to an unpaired electron, are involved in essential cellular functions and play a crucial role in the immune response under normal physiological conditions. However, an imbalance in ROS homeostasis, leading to excessive ROS production, results in oxidative stress (OS), which can cause indiscriminate damage to cellular structures and contribute to the pathogenesis of specific diseases, including OC. OC is primarily classified based on the originating cell type into epithelial, stromal, and germinal tumors, with epithelial tumors being the most prevalent. Despite advancements in medical technology, early detection of OC remains challenging, often leading to delayed treatment initiation. Current therapeutic approaches include surgical excision of tumor tissue, radiotherapy, and chemotherapy. While these treatments are effective in early-stage OC, high mortality rates and frequent relapse underscore the urgent need for novel diagnostic and therapeutic strategies. This review aims to elucidate the role of ROS in OC, emphasizing the potential for developing innovative diagnostic tools and treatments that target ROS-mediated pathways. Given the critical impact of early detection and effective treatment, advancing our understanding of ROS in the context of OC could significantly enhance patient outcomes. Full article

Esophageal cancer (EC) is a very common form of cancer in developing countries, and its exponential progression is a cause for concern. Available treatments face the phenomenon of multi-drug resistance, as well as multiple disabling side effects. The number of deaths is expected to double by 2030 if nothing is done. Due to their high representativeness in plants, phenolic compounds are a potential alternative for halting the spread of this disease, which bereaves many thousands of families every year. This study aims to identify phenolic compounds with activity against esophageal cancer, assess their toxicological profiles, and explore future perspectives. To achieve this, the literature search was meticulously carried out in the Google Scholar, Scopus, Web of Sciences, and Pub-Med/Medline databases, in accordance with the PRISMA 2020 guidelines. The results show that proanthocyanidin and curcumin represent promising therapeutic options, given their significant in vitro and in vivo activity, and their safety in human subjects in clinical trials. Moscatilin, Genistein, and pristimerin have anticancer activities (≤10 µM) very close to those of doxorubicin and 5-FU, although their safety has not yet been fully established. The compounds identified in vivo exhibit highly significant activities compared with the results obtained in vitro, and are sometimes more effective than the molecules conventionally used to treat EC. Generally, with the exceptions of plumbagin, lapachol, and β-lapachone, all other molecules are relatively non-toxic to normal human cells and represent a therapeutic avenue to be explored by pharmaceutical companies in the fight against esophageal cancer. However, more detailed toxicological studies of certain molecules remain a priority. Full article

Cannabis sativa L. has garnered attention as a potential source for new antimicrobial agents, particularly due to the increased prevalence of microbial resistance to conventional antimicrobials and the emergence of multidrug-resistant pathogens. This review, conducted according to the PRISMA 2020 statement, systematically analyzed the antimicrobial properties of C. sativa extracts and cannabinoids against various bacteria, fungi, viruses, and parasites. Data were collected from the scientific literature (102 papers) and clinical trials (5 studies) from 2014 to June 2024. Findings revealed that cannabinoids, especially CBD, demonstrate significant antimicrobial activity against Gram-positive bacteria like MRSA, Gram-negative bacteria such as Pseudomonas aeruginosa, various Candida species, SARS-CoV-2, and HIV. Additionally, CBD showed efficacy against parasitic infections like Echinococcus granulosus and Leishmania species. These results suggest that cannabinoids may represent a new class of antimicrobial agents with unique and diverse mechanisms of action, potentially effective in broad-spectrum therapies. This study highlights the urgent need for further research and standardized clinical trials to validate these findings and to develop cannabinoid-based treatments. The antimicrobial properties of C. sativa align with WHO priorities and support global health initiatives, offering promising avenues for addressing antimicrobial resistance and improving public health outcomes. Full article

Genetic factors influence medication response (pharmacogenetics), affecting the pharmacodynamics and pharmacokinetics of many medicaments used in clinical care. The ability of medications to cross the blood–brain barrier (BBB) represents a critical putative factor in the effectiveness and tolerability of various medications relevant to central nervous system disorders (CNS), cancer, and broader medical conditions at a pharmacokinetic (dosing) level. Pharmacogenetics has the potential to personalise medicine to a greater extent than has been possible, with the potential to help reduce heuristic delays to effective tolerable pharmacotherapy. Here, we critically examine and summarise the evidence, particularly for ABCB1 polymorphisms associated with drug transportation and other clinical relevance. These transporters appear to have a role in BBB pharmacogenetics and may indicate new avenues of research that extend beyond the current paradigm of CYP450 polymorphisms. We identify some of the most promising variants for clinical translation while spotlighting the complexities of the involved systems and limitations of the current empirical literature. Full article

We have synthesized 22 symmetric and asymmetric 4-aryl-1,4-dihydropyridines (1,4-DHPs) by a “green” microwave-assisted one-pot multicomponent Hantzsch reaction and evaluated their cytotoxicity to three human cancer cell lines regarding U-251MG (human glioblastoma), HeLa 229 (human cervical adenocarcinoma), and MCF-7 (human breast carcinoma). None of the 1,4-DHPs were cytotoxic to U-251MG cells. Most of the 1,4-DHPs did not affect HeLa 229 or MCF-7 cell viability. On the other hand, symmetric 1,4-DHPs 18 (diethyl 4-(4-benzyloxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate), 19 (diethyl 4-(4-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate), and 20 (diethyl 4-(3-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) reduced the HeLa (IC₅₀ = 3.6, 2.3, and 4.1 µM, respectively) and MCF-7 (IC₅₀ = 5.2, 5.7, and 11.9 µM, respectively) cell viability. These 1,4-DHPs were more cytotoxic to the HeLa and MCF-7 cells than to the GM07492 (normal human fibroblast) cells, as evidenced by their selectivity indexes. Therefore,1,4-DHPs 18, 19, and 20 may serve as novel lead compounds to discover other 1,4-DHP derivatives with improved anticancer potency and selectivity. Full article

Sex-related differences in psychopharmacology present unique challenges in both clinical and research settings. Recognition of sex differences in psychopharmacological treatment has increased in recent years, but a significant research gap regarding variations between men and women still exists. Biological factors, including hormonal fluctuations, genetic factors, and brain structure differences, contribute significantly to differential drug responses. Moreover, social determinants can influence the differential burden of psychiatric disorders between the sexes and may impact treatment plans. Incorporating sex as a key variable in personalized treatment programs and plans holds the potential to optimize efficacy and minimize adverse effects in psychopharmacology. Sex-related challenges in psychopharmacology necessitate a nuanced approach to treatment. Further research is needed to fully understand these differences and to develop guidelines for personalized medication management. By addressing these challenges, clinicians can improve treatment outcomes and enhance the quality of life of patients with psychiatric disorders. Full article

(1) Background: The SARS-CoV-2 papain-like protease (PLpro) remains an underexplored antiviral target so far. The reduced efficacy of approved treatments against novel variants highlights the importance of developing new agents. This review aims to provide a comprehensive understanding of phytochemicals as inhibitors of PLpro, identify gaps, and propose novel insights for future reference. (2) Methods: A thorough literature search was conducted using Google Scholar, ScienceDirect, and PubMed. Out of 150 articles reviewed, 57 met inclusion criteria, focusing on SARS-CoV-2 PLpro inhibitors, excluding studies on other coronaviruses or solely herbal extracts. Data were presented class-wise, and phytochemicals were grouped into virtual, weak, modest, and potential inhibitors. (3) Results: Approximately 100 phytochemicals are reported in the literature as PLpro inhibitors. We classified them as virtual inhibitors (70), weak inhibitors (13), modest inhibitors (11), and potential inhibitors (6). Flavonoids, terpenoids, and their glycosides predominated. Notably, six phytochemicals, including schaftoside, tanshinones, hypericin, and methyl 3,4-dihydroxybenzoate, emerged as potent PLpro inhibitors with favorable selectivity indices and disease-mitigation potential; (4) Conclusions: PLpro stands as a promising therapeutic target against SARS-CoV-2. The phytochemicals reported in the literature possess valuable drug potential; however, certain experimental and clinical gaps need to be filled to meet the therapeutic needs. Full article

Ampakines are a class of orally available positive allosteric modulators of the AMPA-glutamate receptor (AMPAR) and have therapeutic implications for neurological/neuropsychiatric disorders in which AMPAR signaling is compromised. Low-impact ampakines are a distinct subclass of drugs that only modestly offset receptor desensitization and do not alter agonist binding affinity and thus lack the neurotoxicity and epileptogenic effects associated with other AMPAR modulators. In these studies, we describe the pre-clinical pharmacology of ampakine 1-(benzofurazan-5-ylcarbonyl)morpholine (CX717). CX717 modestly offsets desensitization in hippocampal patches and augments synaptic transmission in vivo. CX717 also enhances long-term potentiation in rats, which is crucial for learning and memory. CX717 enhances performance in the eight-arm radial maze and abrogates amphetamine-induced locomotor activity while being devoid of cataleptic activity in rats. CX717 also ameliorates alfentanil-induced respiratory depression in rats and is not toxic to cultured rat neurons. CX717 is active at doses of 0.3–10 mg/kg and lacked serious adverse events in safety studies in mice up to 2000 mg/kg. CX717 was also previously shown to be safe in humans and effective in reversing opiate-induced respiratory depression and hyperactivity and inattentiveness in adults with ADHD. These findings support the continued clinical investigation of CX717 in the treatment of ADHD, dementia, and opiate-induced respiratory depression. Full article

The membrane impermeability of a drug poses a significant challenge in drug research and development, preventing effective drug delivery to the target site. Specifically, the blood-brain barrier (BBB) presents a formidable obstacle to the delivery of drugs targeting the central nervous system (CNS) into the brain, whereas the blood-retinal barrier (BRB) presents a tremendous obstacle to the delivery of drugs targeting the ocular diseases into the eyes. The development of drugs for Alzheimer’s or Parkinson’s disease targeting the CNS and for diabetic retinopathy and age-related macular degeneration targeting the eyes remains an unmet medical need for patients. Transporters play a crucial physiological role in maintaining homeostasis in metabolic organs. Various types of solute carrier (SLC) transporters are expressed in the capillary endothelial cells of the BBB, facilitating the delivery of nutrients from the blood flow to the brain. Therefore, carrier-mediated transport across the BBB can be achieved using SLC transporters present in capillary endothelial cells. It is well-known that CNS drugs typically incorporate N-containing groups, indicating that cation transporters facilitate their transport into the brain. In fact, carrier-mediated transport across the BBB can be accomplished using glucose transporter type 1 (Glut1) as a glucose transporter, L-type amino acid transporter 1 (LAT1) as a large neutral amino acid transporter, and H⁺/cation antiporter as a cation transporter. Surprisingly, although organic cation transporter novel type 2 (OCTN2) is expressed in the capillary endothelial cells, there has been limited investigation into OCTN2-mediated substance delivery into the brain across the BBB. Furthermore, it is suggested that OCTN2 is expressed at the BRB. In this prospective review, I present the advantages and possibilities of substance delivery into the brain across the BBB or into the eyes across the BRB, mediated by OCTN2 via carrier-mediated transport or receptor-mediated transcytosis. Full article

Breast cancer is the most common type of cancer globally and presents an escalating problem and a huge burden on societies. Several strategies are implemented in clinics to treat patients and prevent disease incidence. Efforts to understand the underlying causes of disease emergence are pivotal, and the latest examination of human transcriptomic studies showed the involvement of the noncoding RNA regulatory molecules in influencing both pathological and physiological conditions. Several molecular mechanisms are involved in the process and collaborate to develop tumor plasticity and drug resistance. In this review, we highlight for the first time the interplay between long noncoding RNAs and Aurora kinases in breast cancer and review the latest advances in the field in an attempt to pave the way for a better understanding of the course of the disease and to delineate the targets for treatment strategies in the clinic. Full article