-
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.
-
2.
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".
-
3.
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.
-
4.
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.
-
5.
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.
-
6.
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.
-
7.
Drug-Induced Hypophosphatemia: Current Insights.
Megapanou, E, Florentin, M, Milionis, H, Elisaf, M, Liamis, G
Drug safety. 2020;(3):197-210
Abstract
Phosphate is actively involved in many important biochemical pathways, such as energy and nucleic acid metabolism, cellular signaling, and bone formation. Hypophosphatemia, defined as serum phosphate levels below 2.5 mg/dL (0.81 mmol/L), is frequently observed in the course of treatment with commonly used drugs, such as diuretics, bisphosphonates, antibiotics, insulin, and antacids. Furthermore, this undesired effect may complicate the use of several novel medications, including teriparatide, denosumab, parenteral iron, and antiviral and antineoplastic agents. This review addresses drug-associated hypophosphatemia, focusing on underlying mechanisms and the most recent knowledge on this topic, in order to increase the insight of clinicians, with reference to early diagnosis and appropriate management.
-
8.
Pharmacokinetics in Patients with Cystic Fibrosis: A Systematic Review of Data Published Between 1999 and 2019.
De Sutter, PJ, Gasthuys, E, Van Braeckel, E, Schelstraete, P, Van Biervliet, S, Van Bocxlaer, J, Vermeulen, A
Clinical pharmacokinetics. 2020;(12):1551-1573
Abstract
BACKGROUND Cystic fibrosis is a lethal inherited disease that affects multiple organs. To provide optimal pharmacological treatment of comorbidities associated with cystic fibrosis, relevant alterations in pharmacokinetics must be known. OBJECTIVE The objective of this study was to compare the pharmacokinetics of drugs between patients with cystic fibrosis and controls, based on clinical study reports published from 1999 to 2019. METHODS Clinical studies were considered if patients with cystic fibrosis and patients without cystic fibrosis/healthy volunteers were included, a drug was administered orally/intravenously and pharmacokinetic parameters were compared. RESULTS In total, 32 clinical studies were included. Twenty-one studies reported absorption parameters. For multiple drugs, speed and/or extent of oral absorption were lower in cystic fibrosis. This phenomenon is possibly related to pathophysiological changes in the gastrointestinal tract associated with cystic fibrosis. However, a large proportion of drugs had comparable absorption kinetics. Twenty-one studies discussed volume of distribution, which was comparable between groups for most drugs. Initial differences became smaller when scaled to body composition. For some highly protein-bound drugs, inflammation-related changes in plasma proteins helped explain residual variability between cystic fibrosis and controls. Twenty-four studies elaborated on clearance, whereby higher clearances were observed in cystic fibrosis. In contrast with previously published reviews, no evidence was found for increased activities of drug-metabolising enzymes nor for up-regulation of active transport processes involved in drug disposition. In most cases, scaling clearance parameters to body composition and/or incorporating differences in plasma protein concentration accounted for these larger clearances. IMPLICATIONS There is no evidence that genetic defects causing cystic fibrosis directly lead to altered pharmacokinetics. However, co-morbidities can have a potential impact on drug absorption and disposition. Because of gastrointestinal complications, it is not advisable to extrapolate drug absorption parameters from healthy volunteers to patients with cystic fibrosis. Differences observed in the volume of distribution and clearance in patients with cystic fibrosis can potentially be explained by correcting for lean body mass.
-
9.
Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology.
Samodelov, SL, Kullak-Ublick, GA, Gai, Z, Visentin, M
International journal of molecular sciences. 2020;(21)
Abstract
Individual cells and epithelia control the chemical exchange with the surrounding environment by the fine-tuned expression, localization, and function of an array of transmembrane proteins that dictate the selective permeability of the lipid bilayer to small molecules, as actual gatekeepers to the interface with the extracellular space. Among the variety of channels, transporters, and pumps that localize to cell membrane, organic cation transporters (OCTs) are considered to be extremely relevant in the transport across the plasma membrane of the majority of the endogenous substances and drugs that are positively charged near or at physiological pH. In humans, the following six organic cation transporters have been characterized in regards to their respective substrates, all belonging to the solute carrier 22 (SLC22) family: the organic cation transporters 1, 2, and 3 (OCT1-3); the organic cation/carnitine transporter novel 1 and 2 (OCTN1 and N2); and the organic cation transporter 6 (OCT6). OCTs are highly expressed on the plasma membrane of polarized epithelia, thus, playing a key role in intestinal absorption and renal reabsorption of nutrients (e.g., choline and carnitine), in the elimination of waste products (e.g., trimethylamine and trimethylamine N-oxide), and in the kinetic profile and therapeutic index of several drugs (e.g., metformin and platinum derivatives). As part of the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations, this article critically presents the physio-pathological, pharmacological, and toxicological roles of OCTs in the tissues in which they are primarily expressed.
-
10.
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.