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1.
New pharmaceuticals approved by FDA in 2020: Small-molecule drugs derived from amino acids and related compounds.
Liu, A, Han, J, Nakano, A, Konno, H, Moriwaki, H, Abe, H, Izawa, K, Soloshonok, VA
Chirality. 2022;(1):86-103
Abstract
Amino acids (AAs) play an important role in the modern health industry as key synthetic precursors for pharmaceuticals, biomaterials, biosensors, and drug delivery systems. Currently, over 30% of small-molecule drugs contain residues of tailor-made AAs or derived from them amino-alcohols and di-amines. In this review article, we profile 12 AA-derived new pharmaceuticals approved by the FDA in 2020. These newly introduced drugs include Tazverik (epithelioid sarcoma), Gemtesa (overactive bladder), Zeposia (multiple sclerosis), Byfavo (induction and maintenance of procedural sedation), Cu 64 dotatate, and Gallium 68 PSMA-11 (both PET imaging), Rimegepant (acute migraine), Zepzelca (lung cancer), Remdesivir (COVID-19), Amisulpride (nausea and vomiting), Setmelanotide (obesity), and Lonafarnib (progeria syndrome). For each compound, we describe the spectrum of biological activity, medicinal chemistry discovery, and synthetic preparation.
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2.
Botanical, Phytochemical, Anti-Microbial and Pharmaceutical Characteristics of Hawthorn (Crataegusmonogyna Jacq.), Rosaceae.
Martinelli, F, Perrone, A, Yousefi, S, Papini, A, Castiglione, S, Guarino, F, Cicatelli, A, Aelaei, M, Arad, N, Gholami, M, et al
Molecules (Basel, Switzerland). 2021;(23)
Abstract
Hawthorn (Crataegus monogyna Jacq.) is a wild edible fruit tree of the genus Crataegus, one of the most interesting genera of the Rosaceae family. This review is the first to consider, all together, the pharmaceutical, phytochemical, functional and therapeutic properties of C. monogyna based on numerous valuable secondary metabolites, including flavonoids, vitamin C, glycoside, anthocyanin, saponin, tannin and antioxidants. Previous reviews dealt with the properties of all species of the entire genera. We highlight the multi-therapeutic role that C. monogyna extracts could have in the treatment of different chronic and degenerative diseases, mainly focusing on flavonoids. In the first part of this comprehensive review, we describe the main botanical characteristics and summarize the studies which have been performed on the morphological and genetic characterization of the C. monogyna germplasm. In the second part, the key metabolites and their nutritional and pharmaceutical properties are described. This work could be an essential resource for promoting future therapeutic formulations based on this natural and potent bioactive plant extract.
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3.
Bell Peppers (Capsicum annum L.) Losses and Wastes: Source for Food and Pharmaceutical Applications.
Anaya-Esparza, LM, Mora, ZV, Vázquez-Paulino, O, Ascencio, F, Villarruel-López, A
Molecules (Basel, Switzerland). 2021;(17)
Abstract
Currently, the high added-value compounds contained in plant by-products and wastes offer a wide spectrum of opportunities for their reuse and valorization, contributing to the circular economy. The bell pepper (Capsicum annum L.) is an exotic vegetable with high nutritional value that, after processing, leaves wastes (peel, seeds, and leaves) that represent desirable raw material for obtaining phytochemical compounds. This review summarizes and discusses the relevant information on the phytochemical profile of bell peppers and their related biological properties as an alternative to revalorize losses and wastes from bell peppers for their application in the food and pharmaceutical industries. Bell pepper fruits, seeds, and leaves contain bioactive compounds (phenols, flavonoids, carotenoids, tocopherol, and pectic polysaccharides) that exhibit antioxidant, antibacterial, antifungal, immunosuppressive and immunostimulant properties, and antidiabetic, antitumoral and neuroprotective activities, and have a potential use as functional food additives. In this context, the revalorization of food waste is positioned as a technological and innovative research area with beneficial effects for the population, the economy, and the environment. Further studies are required to guarantee the safety use of these compounds and to understand their mechanisms of action.
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4.
The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes.
Kell, DB
Molecules (Basel, Switzerland). 2021;(18)
Abstract
Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real biomembranes are mostly protein, not lipid, (ii) unlike purely lipid bilayers that can form transient aqueous channels, the high concentrations of proteins serve to stop such activity, (iii) natural evolution long ago selected against transport methods that just let any undesirable products enter a cell, (iv) transporters have now been identified for all kinds of molecules (even water) that were once thought not to require them, (v) many experiments show a massive variation in the uptake of drugs between different cells, tissues, and organisms, that cannot be explained if lipid bilayer transport is significant or if efflux were the only differentiator, and (vi) many experiments that manipulate the expression level of individual transporters as an independent variable demonstrate their role in drug and nutrient uptake (including in cytotoxicity or adverse drug reactions). This makes such transporters valuable both as a means of targeting drugs (not least anti-infectives) to selected cells or tissues and also as drug targets. The same considerations apply to the exploitation of substrate uptake and product efflux transporters in biotechnology. We are also beginning to recognise that transporters are more promiscuous, and antiporter activity is much more widespread, than had been realised, and that such processes are adaptive (i.e., were selected by natural evolution). The purpose of the present review is to summarise the above, and to rehearse and update readers on recent developments. These developments lead us to retain and indeed to strengthen our contention that for transmembrane pharmaceutical drug transport "phospholipid bilayer transport is negligible".
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5.
Water molecules at protein-drug interfaces: computational prediction and analysis methods.
Samways, ML, Taylor, RD, Bruce Macdonald, HE, Essex, JW
Chemical Society reviews. 2021;(16):9104-9120
Abstract
The fundamental importance of water molecules at drug-protein interfaces is now widely recognised and a significant feature in structure-based drug design. Experimental methods for analysing the role of water in drug binding have many challenges, including the accurate location of bound water molecules in crystal structures, and problems in resolving specific water contributions to binding thermodynamics. Computational analyses of binding site water molecules provide an alternative, and in principle complete, structural and thermodynamic picture, and their use is now commonplace in the pharmaceutical industry. In this review, we describe the computational methodologies that are available and discuss their strengths and weaknesses. Additionally, we provide a critical analysis of the experimental data used to validate the methods, regarding the type and quality of experimental structural data. We also discuss some of the fundamental difficulties of each method and suggest directions for future study.
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6.
Chemical Approaches for Studying the Biology and Pharmacology of Membrane Transporters: The Histidine/Large Amino Acid Transporter SLC7A5 as a Benchmark.
Scalise, M, Scanga, R, Console, L, Galluccio, M, Pochini, L, Indiveri, C
Molecules (Basel, Switzerland). 2021;(21)
Abstract
The localization of membrane transporters at the forefront of natural barriers makes these proteins very interesting due to their involvement in the absorption and distribution of nutrients and xenobiotics, including drugs. Over the years, structure/function relationship studies have been performed employing several strategies, including chemical modification of exposed amino acid residues. These approaches are very meaningful when applied to membrane transporters, given that these proteins are characterized by both hydrophobic and hydrophilic domains with a different degree of accessibility to employed chemicals. Besides basic features, the chemical targeting approaches can disclose information useful for pharmacological applications as well. An eminent example of this picture is the histidine/large amino acid transporter SLC7A5, known as LAT1 (Large Amino Acid Transporter 1). This protein is crucial in cell life because it is responsible for mediating the absorption and distribution of essential amino acids in peculiar body districts, such as the blood brain barrier and placenta. Furthermore, LAT1 can recognize a large variety of molecules of pharmacological interest and is also considered a hot target for drugs due to its over-expression in virtually all human cancers. Therefore, it is not surprising that the chemical targeting approach, coupled with bioinformatics, site-directed mutagenesis and transport assays, proved fundamental in describing features of LAT1 such as the substrate binding site, regulatory domains and interactions with drugs that will be discussed in this review. The results on LAT1 can be considered to have general applicability to other transporters linked with human diseases.
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7.
[Computer-aided drug design: from discovery of novel pharmaceutical agents to systems pharmacology].
Poroikov, VV
Biomeditsinskaia khimiia. 2020;(1):30-41
Abstract
New drug discovery is based on the analysis of public information about the mechanisms of the disease, molecular targets, and ligands, which interaction with the target could lead to the normalization of the pathological process. The available data on diseases, drugs, pharmacological effects, molecular targets, and drug-like substances, taking into account the combinatorics of the associative relations between them, correspond to the Big Data. To analyze such data, the application of computer-aided drug design methods is necessary. An overview of the studies in this area performed by the Laboratory for Structure-Function Based Drug Design of IBMC is presented. We have developed the approaches to identifying promising pharmacological targets, predicting several thousand types of biological activity based on the structural formula of the compound, analyzing protein-ligand interactions based on assessing local similarity of amino acid sequences, identifying likely molecular mechanisms of side effects of drugs, calculating the integral toxicity of drugs taking into account their metabolism, have been developed in the human body, predicting sustainable and sensitive options strains and evaluating the effectiveness of combinations of antiretroviral drugs in patients, taking into account the molecular genetic characteristics of the clinical isolates of HIV-1. Our computer programs are implemented as the web-services freely available on the Internet, which are used by thousands of researchers from many countries of the world to select the most promising substances for the synthesis and determine the priority areas for experimental testing of their biological activity.
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8.
Gut microbiota as an "invisible organ" that modulates the function of drugs.
Li, X, Liu, L, Cao, Z, Li, W, Li, H, Lu, C, Yang, X, Liu, Y
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2020;:109653
Abstract
Gut microbiota plays an important role in the gut and have become a hotspot of recent research interests. Commensal microbiota in gut exert a variety of effects on the host, from shaping the structure and function of the gut and the immune system to the modulation of nutrient status of the host and the treatment outcomes of some drugs. Gut microbiota and its enzyme product and subsequent products, such as short-chain fatty acid and bile acid, play important roles in the biotransformation of drugs via directly or indirectly affecting drug absorption, toxicity, metabolism and bioavailability. Drugs, especially antibiotics, also affect the homeostasis of probiotics and the integrity and function of the intestinal mucosa. These interplaying processes produce a variety of important metabolites of the host and drugs and affect the balance of microbiota and the mucosal barrier then modulate the function of drugs. Gut microbiota imbalance is associated with a broad range of disease mechanisms, and this association denotes a new drug-therapeutic avenue. The present review summarizes how gut microbiota acts as an "invisible organ" to directly or indirectly modulate the function of drugs, on the aspects of probiotic homeostasis, drugs and host nutritional metabolism, AJC, mucus layer and microfold cells.
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9.
Analysis of Scientific Research Driving Microalgae Market Opportunities in Europe.
Rumin, J, Nicolau, E, Junior, RGO, Fuentes-Grünewald, C, Picot, L
Marine drugs. 2020;(5)
Abstract
A bibliographic database of scientific papers published by authors affiliated to research institutions worldwide, especially focused in Europe and in the European Atlantic Area, and containing the keywords "microalga(e)" or "phytoplankton" was built. A corpus of 79,020 publications was obtained and analyzed using the Orbit Intellixir software to characterize the research trends related to microalgae markets, markets opportunities and technologies that could have important impacts on markets evolution. Six major markets opportunities, the production of biofuels, bioplastics, biofertilizers, nutraceuticals, pharmaceuticals and cosmetics, and two fast-evolving technological domains driving markets evolution, microalgae harvesting and extraction technologies and production of genetically modified (GM-)microalgae, were highlighted. We here present an advanced analysis of these research domains to give an updated overview of scientific concepts driving microalgae markets.
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10.
Detection of Beta-Glucan Contamination in Nanotechnology-Based Formulations.
Neun, BW, Cedrone, E, Potter, TM, Crist, RM, Dobrovolskaia, MA
Molecules (Basel, Switzerland). 2020;(15)
Abstract
Understanding the potential contamination of pharmaceutical products with innate immunity modulating impurities (IIMIs) is essential for establishing their safety profiles. IIMIs are a large family of molecules with diverse compositions and structures that contribute to the immune-mediated adverse effects (IMAE) of drug products. Pyrogenicity (the ability to induce fever) and activation of innate immune responses underlying both acute toxicities (e.g., anaphylactoid reactions or pseudoallergy, cytokine storm) and long-term effects (e.g., immunogenicity) are among the IMAE commonly related to IIMI contamination. Endotoxins of gram-negative bacteria are the best-studied IIMIs in that both methodologies for and pitfalls in their detection and quantification are well established. Additionally, regulatory guidance documents and research papers from laboratories worldwide are available on endotoxins. However, less information is currently known about other IIMIs. Herein, we focus on one such IIMI, namely, beta-glucans, and review literature and discuss the experience of the Nanotechnology Characterization Lab (NCL) with the detection of beta-glucans in nanotechnology-based drug products.