Pharmaceuticals

A year after the initial outbreak, the COVID-19 pandemic caused by SARS-CoV-2 virus remains a serious threat to global health, while current treatment options are insufficient to bring major improvements. The aim of this study is to identify repurposable drug candidates with a potential to reverse transcriptomic alterations in the host cells infected by SARS-CoV-2. We have developed a rational computational pipeline to filter publicly available transcriptomic datasets of SARS-CoV-2-infected biosamples based on their responsiveness to the virus, to generate a list of relevant differentially expressed genes, and to identify drug candidates for repurposing using LINCS connectivity map. Pathway enrichment analysis was performed to place the results into biological context. We identified 37 structurally heterogeneous drug candidates and revealed several biological processes as druggable pathways. These pathways include metabolic and biosynthetic processes, cellular developmental processes, immune response and signaling pathways, with steroid metabolic process being targeted by half of the drug candidates. The pipeline developed in this study integrates biological knowledge with rational study design and can be adapted for future more comprehensive studies. Our findings support further investigations of some drugs currently in clinical trials, such as itraconazole and imatinib, and suggest 31 previously unexplored drugs as treatment options for COVID-19. Full article

Several studies have reported neuroprotective effects by natural products. A wide range of natural compounds have been investigated, and some of these may play a beneficial role in Alzheimer’s disease (AD) progression. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have been implicated in AD. In particular, MMP-2 and MMP-9 are able to trigger several neuroinflammatory and neurodegenerative pathways. In this review, we summarize and discuss existing literature on natural marine and terrestrial compounds, as well as their ability to modulate MMP-2 and MMP-9, and we evaluate their potential as therapeutic compounds for neurodegenerative and neuroinflammatory diseases, with a focus on Alzheimer’s disease. Full article

Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, certain MMPs, such as MMP-2, -9, and -13, can be overexpressed in pathological states, including cancer and metastasis. Consequently, the development of MMP inhibitors (MMPIs) has been explored for a long time as a strategy to prevent and hinder metastatic growth, but the important side effects linked to promiscuous inhibition of MMPs prevented the clinical use of MMPIs. Therefore, several strategies were proposed to improve the therapeutic profile of this pharmaceutical class, including improved selectivity toward specific MMP isoforms and targeting of specific organs and tissues. Combining both approaches, we conducted the synthesis and preliminary biological evaluation of a series of (2-aminobenzothiazole)-methyl-1,1-bisphosphonic acids active as selective inhibitors of MMP-13 via in vitro and in silico studies, which could prove useful for the treatment of bone metastases thanks to the bone-targeting capabilities granted by the bisphosphonic acid group. Full article

For the first time, hybrid molecules were synthesized on the basis of lithocholic and (5Z,9Z)-1,14-tetradeca-5,9-dienedicarboxylic acids, obtained in two stages using the homo-cyclomagnesiation reaction of 2-(hepta-5,6-diene-1-yloxy)tetrahydro-2H-pyran at the key stage. The resulting hybrid molecules containing 5Z,9Z-dienoic acids are of interest as novel synthetic biologically active precursors to create modern drugs for the treatment of human oncological diseases. The synthesized hybrid molecules were found to exhibit extremely high in vitro inhibitory activity against human topoisomerase I, which is 2–4 times higher than that of camptothecin, a known topoisomerase I inhibitor. Using flow cytometry and fluorescence microscopy, it was first shown that these new molecules are efficient apoptosis inducers in HeLa, U937, Jurkat, K562, and Hek293 cell cultures. In addition, the results of investigations into the effect of the synthesized acids on mitochondria and studies of possible DNA damage in Jurkat tumor cells are also presented. Full article

For some time, glycopeptide antibiotics have been considered the last line of defense against Methicillin-resistant Staphylococcus aureus (MRSA). However, vancomycin resistance of Gram-positive bacteria is an increasingly emerging worldwide health problem. The mode of action of glycopeptide antibiotics is essentially the binding of peptidoglycan cell-wall fragments terminating in the d-Ala-d-Ala sequence to the carboxylate anion binding pocket of the antibiotic. Dimerization of these antibiotics in aqueous solution was shown to persist and even to enhance the antibacterial effect in a co-operative manner. Some works based on solid state (ss) Nuclear Magnetic Resonance (NMR) studies questioned the presence of dimers under the conditions of ssNMR while in a few cases, higher-order oligomers associated with contiguous back-to-back and face-to-face dimers were observed in the crystal phase. However, it is not proved if such oligomers persist in aqueous solutions. With the aid of ¹⁵N-labelled eremomycin using ¹⁵N relaxation and diffusion NMR methods, we observed tetramers and octamers when the N-Ac-d-Ala-d-Ala dipeptide was added. To the contrary, the N-Ac-d-Ala or (N-Ac)₂-l-Lys-d-Ala-d-Ala tripeptide did not induce higher-order oligomers. These observations are interesting examples of tailored supramolecular self-organization. New antimicrobial tests have also been carried out with these self-assemblies against MRSA and VRE (resistant) strains. Full article

We investigated the comparative age-related efficacy of dimethyl fumarate (DMF) and natalizumab (NTZ) in clinical practice on multiple sclerosis (MS). Research in this area is lacking in the previous literature. In a three-year retrospective and clinical–paraclinical study, we compared 173 DMF patients and 94 NTZ patients with a similar average age (40 years) and disease duration (DD) (10 years). Expanded Disability Status Scale (EDSS) scores were higher in the NTZ group than in the DMF group at 3.5 vs. 2.5, respectively (p = 0.001). However, in both groups, age values correlated with DD (r = 0.42; p < 0.001), EDSS (r = 0.52; p < 0.001) and age at onset (r = 0.18; p < 0.001). Furthermore, age-adjusted Kaplan–Meier curves showed that NTZ-treated subjects maintained a 1.0–3.0 EDSS status score (p = 0.003) more frequently and a 3.5–7.0 score (p = 0.022) significantly less frequently compared with DMF-treated subjects. The EDSS percentage mean difference between NTZ and DMF groups was 81.6%, decreasing inversely with age (r = −0.34; p < 0.001). Finally, high EDSS score values were reached at the age of 39–40 years, regardless of their experimental group. We demonstrated age as a major contributor in disability and response to therapy in current management of MS. Thus, age should be considered in the risk/benefit evaluation in decision making for the disease modifying treatments in MS. Full article

Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK⁺ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. Of particular interest are cases with off-target resistance, for example MET, HER2 or KRAS alterations, which require special therapeutic maneuvers, e.g., inclusion in early clinical trials or off-label administration of respectively targeted drugs. On the other hand, up to approximately half of the patients failing TKI, develop anatomically restricted progression, which can be initially tackled with local ablative measures without switch of systemic therapy. Among the overall biologically favorable ALK⁺ tumors, with a mean tumor mutational burden uniquely below 3 mutations per Mb and the longest survival among NSCLC currently, presence of the EML4-ALK fusion variant 3 and/or TP53 mutations identify high-risk cases with earlier treatment failure and a need for more aggressive surveillance and treatment strategies. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK⁺ tumors. Full article

Xenon magnetic resonance imaging (MRI) provides excellent sensitivity through the combination of spin hyperpolarization and chemical exchange saturation transfer (CEST). To this end, molecular hosts such as cryptophane-A or cucurbit[n]urils provide unique opportunities to design switchable MRI reporters. The concentration determination of such xenon binding sites in samples of unknown dilution remains, however, challenging. Contrary to ¹H CEST agents, an internal reference of a certain host (in this case, cryptophane-A) at micromolar concentration is already sufficient to resolve the entire exchange kinetics information, including an unknown host concentration and the xenon spin exchange rate. Fast echo planar imaging (EPI)-based Hyper-CEST MRI in combination with Bloch–McConnell analysis thus allows quantitative insights to compare the performance of different emerging ultra-sensitive MRI reporters. Full article

Cannabis has been widely used as a medicinal plant for millennia; however, studies related to its main components were first conducted in 1960. Subsequently, laboratories have produced new components and structures related to its active biological properties. Countries that have approved the medicinal use of cannabis impose regulations that govern its clinical and scientific use. One means of administering medicinal cannabis is via a magistral preparation that must have a medical prescription and be prepared in an establishment that meets quality standards to ensure the quantities of its main components, such as tetrahydrocannabinol (THC) and cannabidiol (CBD). Furthermore, suppliers must have a clear indication of its use in the patient before prescription. This review shows the published evidence regarding the clinical use of medicinal cannabis magistral preparations in the management of post-chemotherapy nausea and vomiting, neuropathic pain in multiple sclerosis, and anorexia and cachexia in patients with HIV. Full article

Neuropathic pain in humans arises as a consequence of injury or disease of somatosensory nervous system at peripheral or central level. Peripheral neuropathic pain is more common than central neuropathic pain, and is supposed to result from peripheral mechanisms, following nerve injury. The animal models of neuropathic pain show extensive functional and structural changes occurring in neuronal and non-neuronal cells in response to peripheral nerve injury. These pathological changes following damage lead to peripheral sensitization development, and subsequently to central sensitization initiation with spinal and supraspinal mechanism involved. The aim of this narrative review paper is to discuss the mechanisms engaged in peripheral neuropathic pain generation and maintenance, with special focus on the role of glial, immune, and epithelial cells in peripheral nociception. Based on the preclinical and clinical studies, interactions between neuronal and non-neuronal cells have been described, pointing out at the molecular/cellular underlying mechanisms of neuropathic pain, which might be potentially targeted by topical treatments in clinical practice. The modulation of the complex neuro-immuno-cutaneous interactions in the periphery represents a strategy for the development of new topical analgesics and their utilization in clinical settings. Full article

Since the first characterization of the 5-hydroxytryptamine 2B receptor (5-HT_2BR) in 1992, significant progress has been made in 5-HT_2BR research. Herein, we summarize the biological function, structure, and small-molecule pharmaceutical ligands of the 5-HT_2BR. Emerging evidence has suggested that the 5-HT_2BR is implicated in the regulation of the cardiovascular system, fibrosis disorders, cancer, the gastrointestinal (GI) tract, and the nervous system. Eight crystal complex structures of the 5-HT_2BR bound with different ligands provided great insights into ligand recognition, activation mechanism, and biased signaling. Numerous 5-HT_2BR antagonists have been discovered and developed, and several of them have advanced to clinical trials. It is expected that the novel 5-HT_2BR antagonists with high potency and selectivity will lead to the development of first-in-class drugs in various therapeutic areas. Full article

Regenerative medicine is a field that aims to influence and improvise the processes of tissue repair and restoration and to assist the body to heal and recover. In the field of hard tissue regeneration, bio-inert materials are being predominantly used, and there is a necessity to use bioactive materials that can help in better tissue–implant interactions and facilitate the healing and regeneration process. One such bioactive material that is being focused upon and studied extensively in the past few decades is bioactive glass (BG). The original bioactive glass (45S5) is composed of silicon dioxide, sodium dioxide, calcium oxide, and phosphorus pentoxide and is mainly referred to by its commercial name Bioglass. BG is mainly used for bone tissue regeneration due to its osteoconductivity and osteostimulation properties. The bioactivity of BG, however, is highly dependent on the compositional ratio of certain glass-forming system content. The manipulation of content ratio and the element compositional flexibility of BG-forming network developed other types of bioactive glasses with controllable chemical durability and chemical affinity with bone and bioactivity. This review article mainly discusses the basic information about silica-based bioactive glasses, including their composition, processing, and properties, as well as their medical applications such as in bone regeneration, as bone grafts, and as dental implant coatings. Full article

A set of 12 monosubstituted acetophenone thiosemicarbazone derivatives (TSCs) were synthesized and their inhibitory properties toward tyrosinase activity were tested. Moreover, their ability to inhibit melanogenesis in the B16F10 murine melanoma cell line was studied. In order to investigate the nature of interactions between the enzyme and the inhibitors, molecular docking to the active site was performed. TSCs 5, 6, 8, and 9 revealed a half maximal inhibitory concentration (IC₅₀) below 1 µM. Compound 6 turned out to be the most potent tyrosinase inhibitor. All investigated compounds showed reversible inhibition of competitive or mixed type. The para-substituted TSCs had higher affinity for the enzyme as compared to their ortho- and meta-analogues. All investigated compounds inhibited melanin production in B16F10 cells at the micromolar level. Molecular docking showed that the sulfur atom of the thiourea moiety penetrates the active site and interacts with copper ions. The above outcomes might be helpful in the design of new tyrosinase inhibitors in the food and cosmetic industries. Full article

Telmisartan (TEL, an antihypertensive drug) belongs to Class II of the Biopharmaceutical Classification System (BCS) because of its poor aqueous solubility. In this study, we enhanced the solubility, bioavailability, and stability of TEL through the fabrication of TEL-loaded pH-modulated solid dispersion (TEL pH_M-SD) using hot-melt extrusion (HME) technology. We prepared different TEL pH_M-SD formulations by varying the ratio of the drug (TEL, 10–60% w/w), the hydrophilic polymer (Soluplus^®, 30–90% w/w), and pH-modifier (sodium carbonate, 0–10% w/w). More so, the tablets prepared from an optimized formulation (F8) showed a strikingly improved in vitro dissolution profile (~30-fold) compared to the free drug tablets. The conversion of crystalline TEL to its amorphous state is observed through solid-state characterizations. During the stability study, F8 tablets had a better stability profile compared to the commercial product with F8, showing higher drug content, low moisture content, and negligible physical changes. Moreover, compared to the TEL powder, in vivo pharmacokinetic studies in rats showed superior pharmacokinetic parameters, with maximum serum concentration (C_max) and area under the drug concentration–time curve (AUC₀–_∞) of the TEL pH_M-SD formulation increasing by 6.61- and 5.37-fold, respectively. Collectively, the results from the current study showed that the inclusion of a hydrophilic polymer, pH modulator, and the amorphization of crystalline drugs in solid dispersion prepared by HME can be an effective strategy to improve the solubility and bioavailability of hydrophobic drugs without compromising the drug’s physical stability. Full article

Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure. Full article

In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute respiratory distress syndrome (ARDS). It has been shown that pulmonary fibrosis may be one of the major long-term complications of COVID-19. In animal models, the use of spironolactone was proven to be an important drug in the prevention of pulmonary fibrosis. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide significant benefits concerning COVID-19 infection. The primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS. Spironolactone is a well-known, widely used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). Spironolactone and potassium canrenoate, exerting combined pleiotropic action, may provide a therapeutic benefit to patients with COVID-19 pneumonia through antiandrogen, MR blocking, antifibrotic and anti-hyperinflammatory action. It has been proposed that spironolactone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2 expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action, and therefore it may prove to act as additional protection for patients at highest risk of severe pneumonia. Future prospective clinical trials are warranted to evaluate its therapeutic potential. Full article

Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of currently incurable diseases might offer new treatment strategies based on the inhibition of HERV activities by small molecules or therapeutic antibodies. Full article

The emergence of activatable magnetic resonance (MR) contrast agents has prompted significant interest in the detection of functional markers of diseases, resulting in the creation of a plethora of nanoprobes capable of detecting these biomarkers. These markers are commonly dysregulated in several chronic diseases, specifically select cancers and inflammatory diseases. Recently, the development of redox-sensitive nanoparticle-based contrast agents has gained momentum given advances in medicine linking several inflammatory diseases to redox imbalance. Researchers have pinpointed redox dysregulation as an opportunity to use activatable MR contrast agents to detect and stage several diseases as well as monitor the treatment of inflammatory diseases or conditions. These new classes of agents represent an advancement in the field of MR imaging as they elicit a response to stimuli, creating contrast while providing evidence of biomarker changes and commensurate disease state. Most redox-sensitive nanoparticle-based contrast agents are sensitive to reductive glutathione or oxidative reactive oxygen species. In this review, we will explore recent investigations into redox-activatable, nanoparticle-based MR contrast agent candidates. Full article