-
Discovery Medicine 2021Remdesivir is a broad-spectrum antiviral agent. With the rapid spread of Coronavirus disease 2019 (COVID-19) globally, remdesivir is taking the spotlight for COVID-19...
Remdesivir is a broad-spectrum antiviral agent. With the rapid spread of Coronavirus disease 2019 (COVID-19) globally, remdesivir is taking the spotlight for COVID-19 treatment. Despite the promising signs of anti-CoV activity in several preclinical and clinical studies, more data of remdesivir in the treatment of COVID-19 is still needed for evaluating its efficacy.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34965372
DOI: No ID Found -
Biochemical and Biophysical Research... Jan 2021Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global pandemic. Although great efforts... (Review)
Review
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global pandemic. Although great efforts have been made to develop effective therapeutic interventions, only the nucleotide analog remdesivir was approved for emergency use against COVID-19. Remdesivir targets the RNA-dependent RNA polymerase (RdRp), an essential enzyme for viral RNA replication and a promising drug target for COVID-19. Recently, several structures of RdRp in complex with substrate RNA and remdesivir were reported, providing insights into the mechanisms of RNA recognition by RdRp. These structures also reveal the mechanism of RdRp inhibition by nucleotide inhibitors and offer a molecular template for the development of RdRp-targeting drugs. This review discusses the recognition mechanism of RNA and nucleotide inhibitor by RdRp, and its implication in drug discovery.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Catalytic Domain; Coronavirus RNA-Dependent RNA Polymerase; Drug Discovery; Humans; Nucleic Acid Synthesis Inhibitors; Protein Conformation; RNA, Viral; SARS-CoV-2; Virus Replication; COVID-19 Drug Treatment
PubMed: 32943188
DOI: 10.1016/j.bbrc.2020.08.116 -
Journal of Pharmaceutical and... Feb 2022Remdesivir (REM) is the first antiviral drug (Veklury™) approved by the Food and Drug Administration for the therapy of COVID-19. Due to its poor water solubility, the...
Remdesivir (REM) is the first antiviral drug (Veklury™) approved by the Food and Drug Administration for the therapy of COVID-19. Due to its poor water solubility, the preparation of Veklury™ requires a suitable solubilizing excipient at pH 2 conditions. For this purpose, the final formulation contains the randomly substituted sulfobutylether-β-cyclodextrin (SBEβCD) as a complexing agent. Herein, extensive NMR spectroscopic study with various cyclodextrin (CD) derivatives were conducted to understand the interactions in SBEβCD - REM systems at the molecular level. The pK value of REM has been determined experimentally for the first time, as the protonation state of the aminopyrrolo-triazine moiety can play a key role in CD-REM inclusion complex formation as SBEβCD has permanent negative charges. The UV-pH titration experiments yielded a pK of 3.56, thus the majority of REM bears a positive charge at pH 2.0. NMR experiments were performed on β- and γCD derivatives to determine complex stabilities, stoichiometries and structures. The stability constants were determined by nonlinear curve fitting based on H NMR titrations at pH 2.0, while Job's method was used to determine the stoichiometries. βCD complexes were one order of magnitude more stable than their γCD counterparts. Sulfobutylation resulted in a significant increase in stability and the single isomer derivatives showed unexpectedly high stability values (logK = 4.35 for REM - per-6-SBEβCD). In the case of βCDs, the ethylbutyl-moiety plays a key role in complexation immersing into the βCD cavity, while the phenoxy-moiety overtakes and drives the inclusion of REM in the case of γCDs. This is the first comprehensive study of REM-CD complexation, allowing the design of new CD derivatives with tailored stabilities, thereby aiding the formulation or production and even the analytical characterization of REM.
Topics: Adenosine Monophosphate; Alanine; Cyclodextrins; Humans; SARS-CoV-2; Solubility; COVID-19 Drug Treatment
PubMed: 34856493
DOI: 10.1016/j.jpba.2021.114482 -
Amino Acids Aug 2021Searching for new drugs is still a challenge for science, mainly because of civilization development and globalization which promote the rapid spread of diseases, which...
Searching for new drugs is still a challenge for science, mainly because of civilization development and globalization which promote the rapid spread of diseases, which is particularly dangerous in the case of infectious ones. Moreover, readily available already known antibiotics are often overused or misused, possibly contributing to the increase in the number of multidrug-resistant microorganisms. A consequence of this is the need for new structures of potential drugs. One of them is a benzoxazole moiety, a basic skeleton of a group of fluorescent heterocyclic compounds already widely used in chemistry, industry, and medicine, which is also present in naturally occurring biologically active compounds. Moreover, synthetic benzoxazoles are also biologically active. Considering all of that, a large group of non-proteinogenic amino acids based on 3-(2-benzoxazol-5-yl)alanine skeleton was studied in search for new antimicrobial and anticancer agents. Screening tests revealed that antibacterial potential of 41 compounds studied is not very high; however, they are selective acting only against Gram-positive bacteria (B. subtilis). Moreover, almost half of the studied compounds have antifungal properties, also against pathogens (C. albicans). Most of studied compounds are toxic to both normal and cancer cells. However, in a few cases, toxicity to normal cells is much lower than for cancer cells indicating these compounds as future anticancer agents. The research carried out on such a large group of compounds allowed to establish a structure-activity relationship which enables to select candidates for further modifications, necessary to improve their biological activity and obtain a new lead structure with potential for therapeutic use.
Topics: Alanine; Animals; Candida albicans; Cell Line, Tumor; Drug Screening Assays, Antitumor; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests; Rats; Structure-Activity Relationship
PubMed: 34240252
DOI: 10.1007/s00726-021-03030-7 -
European Review For Medical and... May 2020Hot flushes (HFs) are a very frequent condition in menopausal women, associated with a marked decrease in quality of life, impaired ability to carry on daily activities... (Review)
Review
Hot flushes (HFs) are a very frequent condition in menopausal women, associated with a marked decrease in quality of life, impaired ability to carry on daily activities and sleep disturbances. However, this condition is often only given poor attention in daily practice and in clinical research. Indeed, several treatments for HFs exist. The most effective is considered to be hormone replacement therapy, but this strategy has been associated with a poor risk-benefit ratio given its link with the development of cancer. Other treatments have been tested and are currently used, but they are usually only poorly effective or cannot be recommended in all patients due to potential side effects or interference with other molecules. Therefore, there is a major need for new treatment options for HFs. β-alanine supplementation is widely used for the enhancement of energetic metabolism and is known to be devoid of any relevant adverse effect. BA has also been widely used for the treatment of HFs. This narrative review will discuss the current pharmacological management of HFs and will present the role of β-alanine in this setting.
Topics: Dietary Supplements; Female; Hot Flashes; Humans; Quality of Life; beta-Alanine
PubMed: 32432779
DOI: 10.26355/eurrev_202005_21209 -
Antimicrobial Agents and Chemotherapy Dec 2020Remdesivir was recently approved by the Food and Drug Administration for the treatment of hospitalized patients with coronavirus disease 2019 (COVID-19). Remdesivir is... (Review)
Review
Remdesivir was recently approved by the Food and Drug Administration for the treatment of hospitalized patients with coronavirus disease 2019 (COVID-19). Remdesivir is the prodrug of an adenosine analogue that inhibits viral replication of several RNA virus families, including Preclinical data in animal models of coronavirus diseases, including COVID-19, have demonstrated that early treatment with remdesivir leads to improved survival, decreased lung injury, and decreased levels of viral RNA. Recent clinical data have demonstrated the clinical activity of remdesivir in terms of faster time to recovery in patients with severe COVID-19 and higher odds of improved clinical status in patients with moderate COVID-19. Here, clinical trials published to date are presented and appraised. Remdesivir's potential benefits and its favorable adverse-event profile make it an option for the treatment of COVID-19. This article examines the available literature describing remdesivir's pharmacology, pharmacokinetics, and preclinical and clinical data.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; Breast Feeding; Clinical Trials as Topic; Coronavirus Infections; Female; Humans; Immunocompromised Host; Middle East Respiratory Syndrome Coronavirus; Pregnancy; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33139290
DOI: 10.1128/AAC.01814-20 -
The Lancet. Infectious Diseases Feb 2022
Topics: Adenosine Monophosphate; Alanine; Humans
PubMed: 34534513
DOI: 10.1016/S1473-3099(21)00559-4 -
American Journal of Health-system... Mar 2021This report describes our process of 4 health systems coming together to agree on standard use criteria for remdesivir as a coronavirus disease 2019 (COVID-19) treatment...
PURPOSE
This report describes our process of 4 health systems coming together to agree on standard use criteria for remdesivir as a coronavirus disease 2019 (COVID-19) treatment for patients in Utah. We hope our process provides a framework for remdesivir use in other states and insights on future use of other therapeutic agents that may also be in short supply, such as vaccines and monoclonal antibodies.
SUMMARY
Emergency use authorization (EUA) criteria for COVID-19 treatments often allow for broad use of a treatment relative to limited supplies. Without national criteria, each health system must develop further rationing criteria. Health systems in Utah worked together as part of the state's crisis standards of care workgroup to develop a framework for how to limit the EUA criteria for remdesivir to match available supplies. The 4 largest health systems were represented by infectious diseases specialists, chief medical officers, and pharmacists. The group met several times online and communicated via email over a 9-day period to develop the criteria. The clinicians agreed to use this framework to develop criteria for future therapeutics such as monoclonal antibodies.
CONCLUSION
The unique collaboration of the 4 health systems in Utah led to statewide criteria for use of remdesivir for patients with COVID-19, ensuring similar access to this limited resource for all patients in Utah.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Humans; Pharmacy Service, Hospital; Practice Guidelines as Topic; SARS-CoV-2; Utah; COVID-19 Drug Treatment
PubMed: 33483744
DOI: 10.1093/ajhp/zxab009 -
MBio Apr 2022Alanine metabolism has been suggested as an adaptation strategy to oxygen limitation in organisms ranging from plants to mammals. Within the pulmonary infection...
Alanine metabolism has been suggested as an adaptation strategy to oxygen limitation in organisms ranging from plants to mammals. Within the pulmonary infection microenvironment, Aspergillus fumigatus forms biofilms with steep oxygen gradients defined by regions of oxygen limitation. An alanine aminotransferase, AlaA, was observed to function in alanine catabolism and is required for several aspects of A. fumigatus biofilm physiology. Loss of , or its catalytic activity, results in decreased adherence of biofilms through a defect in the maturation of the extracellular matrix polysaccharide galactosaminogalactan (GAG). Additionally, exposure of cell wall polysaccharides is also impacted by loss of , and loss of AlaA catalytic activity confers increased biofilm susceptibility to echinocandin treatment, which is correlated with enhanced fungicidal activity. The increase in echinocandin susceptibility is specific to biofilms, and chemical inhibition of by the alanine aminotransferase inhibitor β-chloro-l-alanine is sufficient to sensitize A. fumigatus biofilms to echinocandin treatment. Finally, loss of increases susceptibility of A. fumigatus to echinocandin treatment in a murine model of invasive pulmonary aspergillosis. Our results provide insight into the interplay of metabolism, biofilm formation, and antifungal drug resistance in A. fumigatus and describe a mechanism of increasing susceptibility of A. fumigatus biofilms to the echinocandin class of antifungal drugs. Aspergillus fumigatus is a ubiquitous filamentous fungus that causes an array of diseases depending on the immune status of an individual, collectively termed aspergillosis. Antifungal therapy for invasive pulmonary aspergillosis (IPA) or chronic pulmonary aspergillosis (CPA) is limited and too often ineffective. This is in part due to A. fumigatus biofilm formation within the infection environment and the resulting emergent properties, particularly increased antifungal resistance. Thus, insights into biofilm formation and mechanisms driving increased antifungal drug resistance are critical for improving existing therapeutic strategies and development of novel antifungals. In this work, we describe an unexpected observation where alanine metabolism, via the alanine aminotransferase AlaA, is required for several aspects of A. fumigatus biofilm physiology, including resistance of A. fumigatus biofilms to the echinocandin class of antifungal drugs. Importantly, we observed that chemical inhibition of alanine aminotransferases is sufficient to increase echinocandin susceptibility and that loss of increases susceptibility to echinocandin treatment in a murine model of IPA. AlaA is the first gene discovered in A. fumigatus that confers resistance to an antifungal drug specifically in a biofilm context.
Topics: Alanine; Alanine Transaminase; Animals; Antifungal Agents; Aspergillus fumigatus; Biofilms; Disease Models, Animal; Echinocandins; Invasive Pulmonary Aspergillosis; Mammals; Mice; Oxygen
PubMed: 35254131
DOI: 10.1128/mbio.02933-21 -
Journal of Microbiology, Immunology,... Feb 2021Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative viral pathogen of coronavirus disease 2019 (COVID-19), appears to have various clinical... (Review)
Review
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative viral pathogen of coronavirus disease 2019 (COVID-19), appears to have various clinical presentations and may result in severe respiratory failure. The global SARS-CoV-2-associated viral pneumonia pandemic was first reported in December 2019 in China. Based on known pharmacological mechanisms, many therapeutic drugs have been repurposed to target SARS-CoV-2. Among these drugs, remdesivir appears to be the currently most promising according to several clinical trials and reports of compassionate use. In this mini-review, we summarize the current evidence on the efficacy and challenges of remdesivir for the treatment of coronavirus disease 2019 (COVID-19).
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19; China; Clinical Trials as Topic; Humans; Pandemics; Randomized Controlled Trials as Topic; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33060041
DOI: 10.1016/j.jmii.2020.09.002