Structural investigation of 2-naphthyl phenyl ether inhibitors bound to WT and Y181C reverse transcriptase highlights key features of the NNRTI binding site
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99 GENERAL AND MISCELLANEOUS↗
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Biological toxicity and environmental hazards associated with PLGA nanoparticles
There have been tremendous advances in nanotechnology. More recently, the use of nanoparticles has expanded to applications including materials, packaging, energy, and medical uses such as drug delivery, diagnostics, and therapeutics. The American Society for Testing and Materials (ASTM) and the International Organization for Standardization (ISO) define nanoparticles as particles with at least one dimension measuring between 1 and 100 nm (2), but this view is generally too limited, and recommendations have been made to consider all materials with a dimension measuring under 1,000 nm as nanoparticles. The biomedical uses of nanoparticles are particularly promising because of their ability to reach and target various sites and organs. However, some nanoparticles can be composed of toxic materials or are limited by issues of biodistribution and bioaccumulation, which have hampered their use in biomedicine. The copolymer poly lactic-co-glycolic acid (PLGA) has gained use in biomedical applications as a delivery system because it is considered biocompatible and can be formulated with controlled degradation in physiological environments. PLGA has a history in biomedicine that dates to the 1970s when biodegradable sutures were developed using PLGA. In addition, the United States (US) Food and Drug Administration (FDA) and the European Medicine Agency (EMA) have approved various PLGA particle formulations as therapeutic delivery vehicles. Interest in biocompatible materials to deliver a range of therapeutic drugs, proteins, nucleic acids, and other molecules has risen recently. In addition to drug delivery, sustained drug release can be achieved by tuning the physical properties of PLGA, such as the molecular weight, ratio of lactic to glycolic acid, drug concentration, stabilizing molecules, and particle size. Given the rise of nanoparticles, human and environmental exposure to them is inevitable as more applications use free, unbound, and highly mobile particles. Although PLGA is generally considered safe, a detailed understanding of how PLGA and the other components used to help formulate this copolymer into a nanoparticle delivery vehicle is useful for assessing potential harmful effects. Despite recent advances in PLGA nanoparticle formulations, residual stabilizing molecules, inconsistent preparations, and batch-to-batch variations can lead to toxicity. Poor preparations of PLGA can lead to common mechanisms of toxicity observed with nanoparticles, such as inflammation and oxidative stress. Consistency in PLGA formulations and accurate methods to evaluate nanoparticle toxicity are needed to ensure safety. In order to better assess PLGA nanoparticles as non-toxic delivery systems, it is critical to understand their physical and chemical properties and the formulation protocols that may introduce toxic components into particles.
Biology, nanoparticle, toxicity↗
Viral Inhibitors Derived from Macroalgae, Microalgae, and Cyanobacteria: A review of antiviral potential throughout pathogenesis
Viruses are abiotic obligate parasites utilizing complex mechanisms to hijack cellular machinery and reproduce, causing multiple harmful effects in the process. Viruses represent a growing global health concern; at the time of writing, COVID-19 has killed at least two million people around the world and devastated global economies. Lingering concern regarding the virus’ prevalence yet hampers return to normalcy. While catastrophic in and of itself, COVID-19 further heralds in a new era of human-disease interaction characterized by the emergence of novel viruses from natural sources with heretofore unseen frequency. Due to deforestation, population growth, and climate change, we are encountering more viruses that can infect larger groups of people with greater ease and increasingly severe outcomes. The devastation of COVID-19 and forecasts of future human/disease interactions call for a creative reconsideration of global response to infectious disease. There is an urgent need for accessible, cost-effective antiviral (AV) drugs that can be mass-produced and widely distributed to large populations. Development of AV drugs should be informed by a thorough understanding of viral structure and function as well as human biology. To maximize efficacy, minimize cost, and reduce development of drug-resistance, these drugs would ideally operate through a varied set of mechanisms at multiple stages throughout the course of infection. Due to their abundance and diversity, natural compounds are ideal for such comprehensive therapeutic interventions. Promising sources of such drugs are found throughout nature; especially remarkable are the algae, a polyphyletic grouping of phototrophs that produce diverse bioactive compounds. While not much literature has been published on the subject, studies have shown that these compounds exert antiviral effects at different stages of viral pathogenesis. In this review, we follow the course of viral infection in the human body and evaluate the AV effects of algae-derived compounds at each stage. Specifically, we examine the AV activities of algae-derived compounds at the entry of viruses into the body, transport through the body via the lymph and blood, infection of target cells, and immune response. We discuss what is known about algae-derived compounds that may interfere with the infection pathways of SARS-CoV-2; and review which algae are promising sources for AV agents or AV precursors that, with further investigation, may yield life-saving drugs due to their diversity of mechanisms and exceptional pharmaceutical potential.
Algae, antiviral, SARS-CoV-2, seaweed, cyanobacter↗
Improving Traditional Registrational Trial End Points: Development and Application of a Desirability of Outcome Ranking End Point for Complicated Urinary Tract Infection Clinical Trials
Abstract Background Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience. Methods Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTIs). ZEUS compared fosfomycin to piperacillin/tazobactam, APEKS-cUTI compared cefiderocol to imipenem, and DORI-05 compared doripenem to levofloxacin. Using DOOR, we estimated the probability of a more desirable outcome with each investigational antibacterial drug. Results In each RCT, the DOOR distribution was similar and the probability that a patient in the investigational arm would have a more desirable outcome than a patient in the control arm had a 95% confidence interval containing 50%, indicating no significant difference between treatment arms. DOOR facilitated improved understanding of potential trade-offs between clinical efficacy and safety. Partial credit and subgroup analyses also highlight unique attributes of DOOR. Conclusions DOOR can effectively be used in registrational cUTI trials. The DOOR end point presented here can be adapted for other infectious disease syndromes and prospectively incorporated into future clinical trials.
Immunology↗
Enhancing Acute Migraine Treatment: Exploring Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for the Nose-to-Brain Route
Migraine has a high prevalence worldwide and is one of the main disabling neurological diseases in individuals under the age of 50. In general, treatment includes the use of oral analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) for mild attacks, and, for moderate or severe attacks, triptans or 5-HT1B/1D receptor agonists. However, the administration of antimigraine drugs in conventional oral pharmaceutical dosage forms is a challenge, since many molecules have difficulty crossing the blood-brain barrier (BBB) to reach the brain, which leads to bioavailability problems. Efforts have been made to find alternative delivery systems and/or routes for antimigraine drugs. In vivo studies have shown that it is possible to administer drugs directly into the brain via the intranasal (IN) or the nose-to-brain route, thus avoiding the need for the molecules to cross the BBB. In this field, the use of lipid nanoparticles, in particular solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has shown promising results, since they have several advantages for drugs administered via the IN route, including increased absorption and reduced enzymatic degradation, improving bioavailability. Furthermore, SLN and NLC are capable of co-encapsulating drugs, promoting their simultaneous delivery to the site of therapeutic action, which can be a promising approach for the acute migraine treatment. This review highlights the potential of using SLN and NLC to improve the treatment of acute migraine via the nose-to-brain route. First sections describe the pathophysiology and the currently available pharmacological treatment for acute migraine, followed by an outline of the mechanisms underlying the nose-to-brain route. Afterwards, the main features of SLN and NLC and the most recent in vivo studies investigating the use of these nanoparticles for the treatment of acute migraine are presented.
Torres, Joana (ORCID:0000000327276229)↗
Cooperative research and development opportunities with the National Cancer Institute
The Office of Technology Development (OTD) of the National Cancer Institute (NCI) is responsible for negotiating Cooperative Research and Development Agreements (CRADAs), whereby the knowledge resulting from NCI investigators' government-sponsored research is developed in collaboration with universities and/or industry into new products of importance for the diagnosis and treatment of cancer and acquired immunodeficiency syndrome (AIDS). The NCI has recently executed a unique 'clinical trials' CRADA and is developing a model agreement based upon it for the development and commercialization of products for the diagnosis and treatment of cancer and AIDS. NCI drug screening, preclinical testing, clinical trials, and AIDS program capabilities form the basis for this new technology development/technology transfer vehicle. NCI's extensive drug screening program and 'designer foods' program serve as potential sources of investigational new drugs (INDs) and cancer preventatives. Collaborations between NCI and pharmaceutical companies having the facilities, experience, and expertise necessary to develop INDs into approved drugs available to the public are being encouraged where the companies have proprietary rights to INDs, or where NCI has proprietary rights to INDs and invites companies to respond to a collaborator announcement published in the Federal Register. The joint efforts of the NCI and the chosen collaborator are designed to generate the data necessary to obtain pharmaceutic regulatory approval from the Food and Drug Administration (FDA) to market the drugs developed, and thereby make them available to health care providers for the diagnosis and treatment of cancer and AIDS.
Sybert, Kathleen↗
Radiation Exposure Alters Expression of Metabolic Enzyme Genes in Mice
Most administered pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand the effects of spaceflight on the enzymes of the liver and exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. Additionally, it has been previous noted that pre-exposure to small radiation doses seems to confer protection against later and larger radiation doses. This protective power of pre-exposure has been called a priming effect or radioadaptation. This study is an effort to examine the drug metabolizing effects of radioadaptation mechanisms that may be triggered by early exposure to low radiation doses.
Wotring, V. E.↗
Decision Framework for Classifying the State of Knowledge for Pharmaceutical Stability in Spaceflight
The currently approved medication formulary for exploration-class spaceflight missions presently exceeds 200pharmaceuticals. However, these medications' physical and chemical stability during long-term exposure to the spaceflight environment remains uncharacterized. A multi-disciplinary team of pharmacy and spaceflight subject matter experts (SMEs) collaborated to develop a decision framework that will prioritize medications for future stability research. This framework prioritizes the physical stability, drug quality, and safety of the active pharmaceutical ingredient of finished drug products selected for specific design reference mission (DRM) drug formularies. The United States Pharmacopeia (USP) defines drug stability as "the extent to which a drug product retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of its manufacture.1"The candidate medication is assessed by applying a sequence of drug agnostic questions to evaluate the limits of stability information pertinent to spaceflight. The answers to these questions ultimately lead to one of three characterizations: green (not prioritized for further research for this DRM), yellow (requires further literature review/additional studies), or red (not suitable for this DRM based on current knowledge). The decision framework will rely on several information resources to inform the ultimate decision, including the ExMC Pharmacy Information Database, published literature, FDA/drug manufacturer monographs, and USP. The results of this framework will be used to classify the state of knowledge for pharmaceutical stability for any specified DRM and guide future research efforts accordingly. This presentation will provide an overview of how this decision framework was developed, detail the challenges and limitations of the pathways, and discuss how researchers can apply the lessons learned from this project to future work
S Kurian↗
Discovery of a Natural Product That Binds to the Mycobacterium tuberculosis Protein Rv1466 Using Native Mass Spectrometry
Elucidation of the mechanism of action of compounds with cellular bioactivity is important for progressing compounds into future drug development. In recent years, phenotype-based drug discovery has become the dominant approach to drug discovery over target-based drug discovery, which relies on the knowledge of a specific drug target of a disease. Still, when targeting an infectious disease via a high throughput phenotypic assay it is highly advantageous to identifying the compound’s cellular activity. A fraction derived from the plant Polyalthia sp. showed activity against Mycobacterium tuberculosis at 62.5 μge/μL. A known compound, altholactone, was identified from this fraction that showed activity towards M. tuberculosis at an minimum inhibitory concentration (MIC) of 64 μM. Retrospective analysis of a target-based screen against a TB proteome panel using native mass spectrometry established that the active fraction was bound to the mycobacterial protein Rv1466 with an estimated pseudo-Kd of 42.0 ± 6.1 µM. Our findings established Rv1466 as the potential molecular target of altholactone, which is responsible for the observed in vivo toxicity towards M. tuberculosis .
59 BASIC BIOLOGICAL SCIENCES↗
Codelivery of Paclitaxel and Parthenolide in Discoidal Bicelles for a Synergistic Anticancer Effect: Structure Matters
Nanotechnology has long been used to improve the tumor targeting of chemotherapeutics. The structure of these nanocarriers greatly affects their efficacy and toxicity. Herein, structurally stable nanodiscoidal phospholipid bicelles, which are capable of encapsulating anticancer drugs, paclitaxel (PTX) and parthenolide (PTL), are designed. This nanodiscoidal bicelle structure is shown previously to exhibit longer blood circulation, deeper tumor penetration, and increased tumor cell uptake compared with spherical particles of similar compositions. Structural characterization and loading capacity of the PTX‐ and PTL‐ loaded nanodiscs are conducted along with an investigation into the cytotoxicity of the bicelles based on the drug‐to‐lipid ratios of both drugs loaded separately and in combination. A significant synergistic effect between both loaded drugs is also observed in A549 lung cancer and drug‐resistant MDA‐MB‐231 cell lines. An in vivo study using mice bearing subcutaneous A549 tumors shows a long circulation time of the intravenously injected DiR‐loaded bicelles and significant antitumor efficacy of the PTX‐ and PTL‐loaded bicelles. This efficacious self‐assembled nanoparticle system displays great potential as a nanoplatform to codeliver multiple therapeutics or diagnostics for improving cancer therapy.
Rad, Armin Tahmasbi↗
Understanding syringeability and injectability of high molecular weight PEO solution through time-dependent force-distance profiles
Opioid medications play a vital role in treating moderate to severe pain. Unfortunately, many drug misusers and abusers attempt to alter the formulations or properties of these drugs by manipulation, (e.g., crushing, chewing, smoking, snorting, injecting). The intravenous (IV) route is most dangerous to abusers, as the drugs directly enter the circulatory system and produce intense euphoria. To obtain a full understanding of the impact of syringe factors (e.g., needle gauge size, needle length, syringe barrel size), on the ease of injection, we undertook a comprehensive assessment of syringeability and injectability of manipulated abuse-deterrent formulations (ADFs). A texture analyzer-based testing method was developed for the measurement of the resistance force of pulling, holding, and pushing phases of injections. Results showed that the finer needle gauge sizes required higher injection force to withdraw drug solutions. In addition, the syringed liquid volume was highly dependent on needle gauge size, holding time, and sample viscosity. In most cases, a lower needle gauge number and a longer holding time increased the syringed volume. Needle length was highly correlated to injection force (R 2 = 0.99). Using longer needles to inject drug solution requires greater force. Furthermore, large barrel size was correlated to pushing force (R 2 = 0.99); thus, increasing the difficulty of pushing the plunger of a large syringe with one hand. Lastly, relationships between injection force, sample viscosity, and testing conditions were elucidated using a mathematical model, which could be used in the future to assess and predict injection force of solution samples.
60 APPLIED LIFE SCIENCES↗
Elucidating the Gas-Phase Behavior of Nitazene Analog Protomers Using Structures for Lossless Ion Manipulations Ion Mobility-Orbitrap Mass Spectrometry
2-benzylbenzimidazoles, or “nitazenes”, are a class of novel synthetic opioids (NSOs) that are increasingly being detected alongside fentanyl analogs and other opioids in drug overdose cases. Nitazenes can be 20x more potent than fentanyl but are not routinely tested for during postmortem or clinical toxicology drug screens; thus, their prevalence in drug overdose cases may be under-reported. Traditional analytical workflows utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS) often require additional confirmation with authentic reference standards to identify a novel nitazene. However, additional analytical measurements with ion mobility spectrometry (IMS) may provide a path towards reference-free identification, which would greatly accelerate NSO identification rates in toxicology labs. Presented here are the first IMS and collision cross section (CCS) measurements on a set of fourteen nitazene analogs using a Structures for Lossless Ion Manipulations (SLIM)-Orbitrap MS. All nitazenes exhibited two high intensity baseline-separated IMS distributions, which fentanyls and other drug and drug-like compounds also exhibit. Incorporating water into the electrospray ionization (ESI) solution caused the intensities of the higher mobility IMS distributions to increase the intensities of the lower mobility IMS distributions to decrease. Nitazenes lacking a nitro group at the R1 position exhibited the greatest shifts in signal intensities due to water. Furthermore, IMS-MS/MS experiments showed that the higher mobility IMS distributions of all nitazenes produced fragment ions with m/z 72, 100, and other low intensity fragments while the lower mobility IMS distributions only produced fragment ions with m/z 72 and 100. The IMS, solvent, and fragmentation studies provide experimental evidence that nitazenes potentially exhibit three gas-phase protomers. In conclusion, the cyclic IMS capability of SLIM was also employed to partially resolve four sets of structurally similar nitazene isomers (e.g., protonitazene/isotonitazene, butonitazene/isobutonitazene/secbutonitazene), showcasing the potential of using high-resolution IMS separations in MS-based workflows for reference-free identification of emerging nitazenes and other NSOs.
46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
Preparation of cyclohexene isotopologues and stereoisotopomers from benzene
The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine1. Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules1. Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington’s disease2, was recently approved by the United States’ Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial1,3,4. The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound5, improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug6,7, these processes are often unselective and the stereoisotopic purity can be difficult to measure7,8. Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Genome-scale metabolic reconstruction of 7,302 human microorganisms for personalized medicine
The human microbiome influences the efficacy and safety of a wide variety of commonly prescribed drugs. Designing precision medicine approaches that incorporate microbial metabolism would require strain- and molecule-resolved, scalable computational modeling. Here, we extend our previous resource of genome-scale metabolic reconstructions of human gut microorganisms with a greatly expanded version. AGORA2 (assembly of gut organisms through reconstruction and analysis, version 2) accounts for 7,302 strains, includes strain-resolved drug degradation and biotransformation capabilities for 98 drugs, and was extensively curated based on comparative genomics and literature searches. The microbial reconstructions performed very well against three independently assembled experimental datasets with an accuracy of 0.72 to 0.84, surpassing other reconstruction resources and predicted known microbial drug transformations with an accuracy of 0.81. We demonstrate that AGORA2 enables personalized, strain-resolved modeling by predicting the drug conversion potential of the gut microbiomes from 616 patients with colorectal cancer and controls, which greatly varied between individuals and correlated with age, sex, body mass index and disease stages. AGORA2 serves as a knowledge base for the human microbiome and paves the way to personalized, predictive analysis of host–microbiome metabolic interactions.
59 BASIC BIOLOGICAL SCIENCES↗
A deep generative model enables automated structure elucidation of novel psychoactive substances
Over the past decade, the illicit drug market has been reshaped by the proliferation of clandestinely produced designer drugs. These agents, referred to as new psychoactive substances (NPSs), are designed to mimic the physiological actions of better-known drugs of abuse while skirting drug control laws. The public health burden of NPS abuse obliges toxicological, police and customs laboratories to screen for them in law enforcement seizures and biological samples. However, the identification of emerging NPSs is challenging due to the chemical diversity of these substances and the fleeting nature of their appearance on the illicit market. Here, in this study, we present DarkNPS, a deep learning-enabled approach to automatically elucidate the structures of unidentified designer drugs using only mass spectrometric data. Our method employs a deep generative model to learn a statistical probability distribution over unobserved structures, which we term the structural prior. We show that the structural prior allows DarkNPS to elucidate the exact chemical structure of an unidentified NPS with an accuracy of 51% and a top-10 accuracy of 86%. Our generative approach has the potential to enable de novo structure elucidation for other types of small molecules that are routinely analysed by mass spectrometry.
Cheminformatics↗
Zap1 is required for Candida glabrata response to fluconazole
ABSTRACT The increasing prevalence of fluconazole-resistant clinical isolates of Candida spp. strongly hinders the widespread use of the drug. To tackle this problem, great efforts have been made to fully understand the fungal response to fluconazole. In this work, we show that the role of Zap1 in Candida glabrata goes beyond regulating yeast adaptation to zinc deficiency. In line with our previous observation that deletion of ZAP1 makes yeast cells more sensitive to fluconazole, we found that the mutant CgΔzap1 accumulates higher levels of the drug, which correlates well with its lower levels of ergosterol. Surprisingly, Zap1 is a negative regulator of the drug efflux transporter gene CDR1 and of its regulator, PDR1. The apparent paradox of drug accumulation in cells where genes encoding transporters relevant for drug extrusion are being overexpressed led us to postulate that their activity could be impaired. In agreement, Zap1-depleted cells present, in addition to decreased ergosterol levels, an altered composition of membrane phospholipids, which together should impact membrane function and impair the detoxification of fluconazole. Overall, our study brings to light Zap1 as an important hub in Candida glabrata response to fluconazole.
Gaspar-Cordeiro, A. (ORCID:0000000202488965)↗
Supercomputing Pipelines Search for Therapeutics Against COVID-19
The urgent search for drugs to combat SARS-CoV-2 has included the use of supercomputers. The use of general-purpose graphical processing units (GPUs), massive parallelism, and new software for high-performance computing (HPC) has allowed researchers to search the vast chemical space of potential drugs faster than ever before. We developed a new drug discovery pipeline using the Summit supercomputer at Oak Ridge National Laboratory to help pioneer this effort, with new platforms that incorporate GPU-accelerated simulation and allow for the virtual screening of billions of potential drug compounds in days compared to weeks or months for their ability to inhibit SARS-COV-2 proteins. Here, this effort will accelerate the process of developing drugs to combat the current COVID-19 pandemic and other diseases.
60 APPLIED LIFE SCIENCES↗