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Current Drug Targets 2021Since its initial start in December 2019 at Wuhan, China, the coronavirus disease 2019 (COVID-19) has been rapidly spreading and labelled as a pandemic by the World... (Review)
Review
BACKGROUND
Since its initial start in December 2019 at Wuhan, China, the coronavirus disease 2019 (COVID-19) has been rapidly spreading and labelled as a pandemic by the World Health Organization. The rate of human to human transmission of COVID-19 is far higher than severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome coronavirus (MERS). With no drugs or vaccines approved for the treatment of the disease, physicians have been using pre-existing drugs to curb the disease. One potential anti-viral agent currently undergoing numerous clinical trials is remdesivir, a nucleotide analog that inhibits RNA-dependent RNA polymerase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
OBJECTIVE
In this mini-review, we provide an overview of remdesivir's journey, mechanism of action, pharmacokinetics, used in patients with COVID-19 under compassionate use principle and clinical trials to understand the effect of remdesivir in the treatment of patients with COVID-19.
CONCLUSION
Initially, remdesivir was granted an emergency use authorization (EUA) by the U.S. Food and Drug Administration for the treatment of COVID-19 with severe disease. But now, remdesivir has been granted for use under EUA to treat all hospitalized COVID-19 patients, irrespective of their severity of disease.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19; Clinical Trials as Topic; Compassionate Use Trials; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33267759
DOI: 10.2174/1389450121999201202110303 -
Angewandte Chemie (International Ed. in... May 2020Bacterial phosphothreonine lyases, or phospholyases, catalyze a unique post-translational modification that introduces dehydrobutyrine (Dhb) or dehydroalanine (Dha) in...
Bacterial phosphothreonine lyases, or phospholyases, catalyze a unique post-translational modification that introduces dehydrobutyrine (Dhb) or dehydroalanine (Dha) in place of phosphothreonine or phosphoserine residues, respectively. We report the use of a phospha-Michael reaction to label proteins and peptides modified with Dha or Dhb. We demonstrate that a nucleophilic phosphine probe is able to modify Dhb-containing proteins and peptides that were recalcitrant to reaction with thiol or amine nucleophiles under mild aqueous conditions. Furthermore, we used this reaction to detect multiple Dhb-modified proteins in mammalian cell lysates, including histone H3, a previously unknown target of phospholyases. This method should prove useful for identifying new phospholyase targets, profiling the biomarkers of bacterial infection, and developing enzyme-mediated strategies for bioorthogonal labeling in living cells.
Topics: Alanine; Amines; Aminobutyrates; Bacteria; Bacterial Infections; Biomarkers; Histones; Humans; Lyases; Phosphines; Phosphothreonine; Protein Processing, Post-Translational; Sulfhydryl Compounds
PubMed: 32196905
DOI: 10.1002/anie.202003631 -
Angewandte Chemie (International Ed. in... Mar 2020The formation of a N-N bond is a unique biochemical transformation, and nature employs diverse biosynthetic strategies to activate nitrogen for bond formation. Among...
The formation of a N-N bond is a unique biochemical transformation, and nature employs diverse biosynthetic strategies to activate nitrogen for bond formation. Among molecules that contain a N-N bond, biosynthetic routes to diazeniumdiolates remain enigmatic. We here report the biosynthetic pathway for the diazeniumdiolate-containing amino acid l-alanosine. Our work reveals that the two nitrogen atoms in the diazeniumdiolate of l-alanosine arise from glutamic acid and aspartic acid, and we clarify the early steps of the biosynthetic pathway by using both in vitro and in vivo approaches. Our work demonstrates a peptidyl-carrier-protein-based mechanism for activation of the precursor l-diaminopropionate, and we also show that nitric oxide can participate in non-enzymatic diazeniumdiolate formation. Furthermore, we demonstrate that the gene alnA, which encodes a fusion protein with an N-terminal cupin domain and a C-terminal AraC-like DNA-binding domain, is required for alanosine biosynthesis.
Topics: Alanine; Aspartic Acid; Glutamic Acid; Molecular Structure; Multigene Family; Streptomyces
PubMed: 31823464
DOI: 10.1002/anie.201913458 -
Expert Review of Respiratory Medicine Apr 2021: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is well known as a novel member of the coronavirus family which caused a sudden outbreak of Coronavirus... (Review)
Review
: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is well known as a novel member of the coronavirus family which caused a sudden outbreak of Coronavirus disease-2019 (COVID-19) in China that quickly developed into a global pandemic. No effective approaches are found as yet for the therapy and epidemiological control of this new virus. We searched the literature in PubMed, Scopus, Web of Knowledge, Google Scholar, and MeSH, for articles and abstracts describing SARS-CoV-2, COVID-19, pneumonia, clinical trials, drug, treatment, and medicine.: The present study aimed to comprehensively overview the current literature on effective anti-SARS-CoV-2 drugs.: Since the beginning of this pandemic disease, many studies have been conducted to find effective drugs to prevent COVID-19, because there are no specific drugs for the treatment of this disease. Most of these drugs with the antiviral potential effect toward COVID-19 are already used as the treatment of other infectious diseases. Some drugs that show the promising therapeutic potential in the initial clinical studies include remdesivir as an inhibitor of RNA-dependent RNA polymerase and favipiravir as an inhibitor of virus replication. Currently, remdesivir received the FDA authorizes to use as an experimental drug for emergency use in COVID-19 patients.
Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Drug Development; Humans; Pandemics; Pyrazines; COVID-19 Drug Treatment
PubMed: 33215942
DOI: 10.1080/17476348.2021.1854092 -
Molecules (Basel, Switzerland) Mar 2023We report the short synthesis of novel -nucleoside Remdesivir analogues, their cytotoxicity and an in vitro evaluation against SARS-CoV-2 (CoV2). The described compounds...
We report the short synthesis of novel -nucleoside Remdesivir analogues, their cytotoxicity and an in vitro evaluation against SARS-CoV-2 (CoV2). The described compounds are nucleoside analogues bearing a nitrogen heterocycle as purine analogues. The hybrid structures described herein are designed to enhance the anti-CoV2 activity of Remdesivir. The compounds were evaluated for their cytotoxicity and their anti-CoV2 effect. We discuss the impact of combining both sugar and base modifications on the biological activities of these compounds, their lack of cytotoxicity and their antiviral efficacy.
Topics: Humans; SARS-CoV-2; COVID-19; COVID-19 Drug Treatment; Antiviral Agents; Alanine
PubMed: 36985586
DOI: 10.3390/molecules28062616 -
Molecular Therapy : the Journal of the... Feb 2021Antiviral drug development for coronavirus disease 2019 (COVID-19) is occurring at an unprecedented pace, yet there are still limited therapeutic options for treating...
Antiviral drug development for coronavirus disease 2019 (COVID-19) is occurring at an unprecedented pace, yet there are still limited therapeutic options for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2, thus generating better antiviral efficacy. Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro. Sixteen synergistic and eight antagonistic combinations were identified; among 16 synergistic cases, combinations of the US Food and Drug Administration (FDA)-approved drug nitazoxanide with remdesivir, amodiaquine, or umifenovir were most notable, all exhibiting significant synergy against SARS-CoV-2 in a cell model. However, the combination of remdesivir and lysosomotropic drugs, such as hydroxychloroquine, demonstrated strong antagonism. Overall, these results highlight the utility of drug repurposing and preclinical testing of drug combinations for discovering potential therapies to treat COVID-19.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Drug Combinations; Drug Synergism; Humans; Hydroxychloroquine; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33333292
DOI: 10.1016/j.ymthe.2020.12.016 -
Revista Espanola de Quimioterapia :... Apr 2022
Topics: Adenosine Monophosphate; Alanine; Humans
PubMed: 35118854
DOI: 10.37201/req/147.2021 -
Nutrients Mar 2023(1) Background: Exercise is effective in promoting and maintaining bone mass. The aim of this study was to detect the exercise-induced metabolic changes in bone tissue...
(1) Background: Exercise is effective in promoting and maintaining bone mass. The aim of this study was to detect the exercise-induced metabolic changes in bone tissue of zebrafish. (2) Methods: Thirty-eight zebrafish (Danio rerio, six months old) were analyzed. The exercise group ( = 19) received 8 weeks of counter-current swimming training. The control group ( = 19) was not subjected to exercise. Mineralization was quantified, and alkaline phosphatase (Alp) and anti-tartrate acid phosphatase (Trap) activities were estimated ( = 12). The metabolomics ( = 12) and transcriptomics ( = 14) data of bone tissue were used for the integration analyses. (3) Results: The results showed that the exercise training improved the bone mineralization of zebrafish, e.g., the exercise group (5.74 × 10 ± 7.63 × 10) had a higher mean optical density than the control group (5.26 × 10 ± 8.56 × 10, = 0.046) for the caudal vertebrae. The amount of mineralized matrix in scales of the exercised zebrafish was also higher (0.156 ± 0.012 vs. 0.102 ± 0.003, = 0.005). Both histological staining and biochemical analysis revealed increased Alp activity (0.81 ± 0.26 vs. 0.76 ± 0.01, = 0.002) and decreased Trap activity (1.34 ± 0.01 vs. 1.36 ± 0.01, = 0.005) in the exercise group. A total of 103 different metabolites (DMs, VIP ≥ 1, fold change (FC) ≥ 1.20 or ≤0.83, < 0.050) were identified. Alanine, aspartate and glutamate metabolism, β-alanine metabolism, pyrimidine metabolism, and pantothenate and CoA biosynthesis were the significantly enriched metabolic pathways ( < 0.050). A total of 35 genes ( ≤ 0.050 (BH), |Log2FC| ≥ 0.5) were coenriched with the 103 DMs in the four identified pathways. Protein-protein interaction network analysis of the 35 genes showed that , , and were the core genes. (4) Conclusions: The results of this study suggest that alanine, aspartate and glutamate metabolism, β-alanine metabolism, pyrimidine metabolism, and pantothenate and CoA biosynthesis contributed to exercise-induced improvements in bone mass.
Topics: Animals; Zebrafish; Transcriptome; Aspartic Acid; Metabolomics; Alanine; beta-Alanine; Pyrimidines; Glutamates
PubMed: 37049535
DOI: 10.3390/nu15071694 -
Alimentary Pharmacology & Therapeutics Jun 2022
Topics: Adenosine Monophosphate; Alanine; Humans; Kidney; Liver
PubMed: 35538355
DOI: 10.1111/apt.16921 -
Health Physics Oct 2022This work investigates alanine powder, an inexpensive and versatile material compared to alanine pellets, as a standardized dosimeter for the alanine-EPR system using a...
This work investigates alanine powder, an inexpensive and versatile material compared to alanine pellets, as a standardized dosimeter for the alanine-EPR system using a Bruker EMX-Micro spectrometer. The feasibility of this method was investigated, and a calibration curve was produced using 40 dosimeters, which were prepared by tightly packing DL-alanine powder in polypropylene microcentrifuge tubes. The dosimeters were irradiated to doses ranging from 0.2-20 Gy using a 60 Co source. A dosimeter handling and measurement protocol was established for all dosimeters. The dosimetric signal was evaluated by measuring the peak-to-peak height of the central resonance peak, and the dose response of alanine powder dosimeters showed a linear behavior in the investigated dose range with relative errors below 13%. Measurement repeatability and reproducibility were tested to show the errors associated with sample placement in the cavity and with the overall measurement method, with both tests showing relative errors below 7%. As an inexpensive material compared to pellet dosimeters, alanine powder has a strong potential to be used as a standardized material for radiation dosimetry applications. The scope of this work is to present an effective and comprehensive methodology with accompanying analysis scripts for dosimetry with alanine powder that is useful in a wide range of applications and dose requirements.
Topics: Alanine; Electron Spin Resonance Spectroscopy; Powders; Radiometry; Reproducibility of Results
PubMed: 35700079
DOI: 10.1097/HP.0000000000001588