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CMAJ : Canadian Medical Association... May 2022
Randomized Controlled Trial
Topics: Adenosine Monophosphate; Alanine; Humans; COVID-19 Drug Treatment
PubMed: 35609913
DOI: 10.1503/cmaj.211698-f -
Journal of Industrial Microbiology &... Apr 2022L-alanine is extensively used in chemical, food, and medicine industries. Industrial production of L-alanine has been mainly based on the enzymatic process using... (Review)
Review
L-alanine is extensively used in chemical, food, and medicine industries. Industrial production of L-alanine has been mainly based on the enzymatic process using petroleum-based L-aspartic acid as the substrate. L-alanine production from renewable biomass using microbial fermentation process is an alternative route. Many microorganisms can naturally produce L-alanine using aminotransferase or L-alanine dehydrogenase. However, production of L-alanine using the native strains has been limited due to their low yields and productivities. In this review, metabolic engineering of microorganisms for L-alanine production was summarized. Among them, the Escherichia coli strains developed by Dr. Lonnie Ingram's group which can produce L-alanine with anaerobic fermentation process had several advantages, especially having high L-alanine yield, and it was the first one that realized commercialization. L-alanine is also the first amino acid that could be industrially produced by anaerobic fermentation.
Topics: Alanine; Biomass; Escherichia coli; Fermentation; Metabolic Engineering
PubMed: 34410417
DOI: 10.1093/jimb/kuab057 -
Biochemical and Biophysical Research... Jan 2021Human coronaviruses (HCoV) were discovered in the 1960s and were originally thought to cause only mild upper respiratory tract diseases in immunocompetent hosts. This... (Review)
Review
Human coronaviruses (HCoV) were discovered in the 1960s and were originally thought to cause only mild upper respiratory tract diseases in immunocompetent hosts. This view changed since the beginning of this century, with the 2002 SARS (severe acute respiratory syndrome) epidemic and the 2012 MERS (Middle East respiratory syndrome) outbreak, two zoonotic infections that resulted in mortality rates of approximately 10% and 35%, respectively. Despite the importance of these pathogens, no approved antiviral drugs for the treatment of human coronavirus infections became available. However, remdesivir, a nucleotide analogue prodrug originally developed for the treatment of Ebola virus, was found to inhibit the replication of a wide range of human and animal coronaviruses in vitro and in preclinical studies. It is therefore not surprising that when the highly pathogenic SARS-CoV-2 coronavirus emerged in late 2019 in China, causing global health concern due to the virus strong human-to-human transmission ability, remdesivir was one of the first clinical candidates that received attention. After in vitro studies had shown its antiviral activity against SARS-CoV-2, and a first patient was successfully treated with the drug in the USA, a number of trials on remdesivir were initiated. Several had encouraging results, particularly the ACTT-1 double blind, randomized, and placebo controlled trial that has shown shortening of the time to recovery in hospitalized patients treated with remdesivir. The results of other trials were instead negative. Here, we provide an overview of remdesivir discovery, molecular mechanism of action, and initial and current clinical studies on its efficacy.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Drug Discovery; Hemorrhagic Fever, Ebola; Humans; COVID-19 Drug Treatment
PubMed: 33388129
DOI: 10.1016/j.bbrc.2020.11.043 -
Drugs Sep 2020The antiviral agent remdesivir (Veklury; Gilead Sciences), nucleotide analogue prodrug, has broad-spectrum activity against viruses from several families. Having... (Review)
Review
The antiviral agent remdesivir (Veklury; Gilead Sciences), nucleotide analogue prodrug, has broad-spectrum activity against viruses from several families. Having demonstrated potent antiviral activity against coronaviruses in preclinical studies, remdesivir emerged as a candidate drug for the treatment of the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, during the current global pandemic. Phase III evaluation of remdesivir in the treatment of COVID-19 commenced in early 2020 and has thus far yielded promising results. In late May 2020, Taiwan conditionally approved the use of remdesivir in patients with severe COVID-19. This was followed by a rapid succession of conditional approvals in various countries/regions including the EU and Canada. Preceding these conditional approvals, an emergency use authorization for remdesivir had been granted in the USA (on 1 May 2020) and a special approval for emergency use was granted in Japan (on 7 May 2020). This article summarizes the milestones in the development of remdesivir leading to its first conditional approval for the treatment of COVID-19.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Drug Development; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2
PubMed: 32870481
DOI: 10.1007/s40265-020-01378-w -
Nutrients Mar 2022Cockscomb hydrolysate was found to have neurite outgrowth-promoting activity in PC12 cells. To investigate the neurite outgrowth-promoting compounds derived from...
Cockscomb hydrolysate was found to have neurite outgrowth-promoting activity in PC12 cells. To investigate the neurite outgrowth-promoting compounds derived from cockscomb hydrolysate, bioassay-guided purification was carried out. Purified active fractions were obtained by liquid-liquid partition, followed by column chromatography. High-performance liquid chromatography and proton nuclear magnetic resonance analyses of the purified active fractions clarified that the main compounds are threonine, alanine, valine, and methionine. By screening for 20 kinds of amino acids, it was shown that valine and methionine, but not threonine and alanine, have neurite outgrowth-promoting activity. The results of activity evaluation of the mixture of amino acids indicated that alanine enhanced the activity of valine and that the mixture of valine and methionine showed a higher ratio of neurite formation than did each of them alone. On the other hand, dipeptides formed by valine and methionine showed weak neurite outgrowth-promoting activity. A mixture of threonine, alanine, valine, and methionine at the same concentrations as those in cockscomb hydrolysate showed neurite outgrowth-promoting activity comparable to that of cockscomb hydrolysate although threonine, alanine, valine, and methionine alone did not show activity at their concentrations in cockscomb hydrolysate. Therefore, the strong neurite outgrowth-promoting activity of cockscomb hydrolysate was considered to be due to the synergistic effect of threonine, alanine, valine, and methionine.
Topics: Alanine; Amino Acids; Animals; Methionine; Neurites; Neuronal Outgrowth; PC12 Cells; Rats; Threonine; Valine
PubMed: 35406035
DOI: 10.3390/nu14071422 -
European Review For Medical and... Sep 2020Remdesivir is a nucleotide analogue prodrug that inhibits viral RNA polymerases. It has been recognized recently as a promising antiviral drug against a wide array of... (Review)
Review
OBJECTIVE
Remdesivir is a nucleotide analogue prodrug that inhibits viral RNA polymerases. It has been recognized recently as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV5). We aimed at determining which drugs used in dentistry interact with Remdesivir in order to avoid adverse reactions that may worsen the condition of patients with COVID-19.
MATERIALS AND METHODS
A literature review was conducted to identify potential drug interactions between remdesivir (used in the treatment of COVID-19) and drugs prescribed in dentistry. The search was made in the databases PubMed and MEDLINE and official websites using key terms remdesivir, drug interactions and dentistry for articles published up to 31st July 2020.
RESULTS
According to the articles reviewed, a total of 279 drugs interact with Remdesivir. Two major interactions have been reported, 277 moderate drug interactions, and one with alcohol/food. The drug interactions involving drugs prescribed in dentistry are all moderate drug interactions and are (according to drug group): (1) antibiotics: azithromycin, clavulanate, doxycycline, erythromycin, levofloxacin; (2) antifungals: clotrimazole, fluconazole, itraconazole, ketoconazole; (3) non-steroidal anti-inflammatories (NAIDS): celecoxib diclofenac, etodolac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, mefenamic acid, naproxen, piroxicam.
CONCLUSIONS
It is clinically necessary for oral health professionals to be aware of possible drug interactions that may occur between remdesivir and drugs commonly prescribed in dentistry in order to prevent adverse reactions that may even endanger the life of a patient with COVID-19.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Dentistry; Drug Interactions; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2
PubMed: 33015819
DOI: 10.26355/eurrev_202009_23065 -
The Journal of Biological Chemistry Apr 2020The nucleotide analogue remdesivir is an investigational drug for the treatment of human coronavirus infection. Remdesivir is a phosphoramidate prodrug and is known to...
The nucleotide analogue remdesivir is an investigational drug for the treatment of human coronavirus infection. Remdesivir is a phosphoramidate prodrug and is known to target viral RNA-dependent RNA polymerases. In this issue, Gordon identify that remdesivir acts as a delayed RNA chain terminator for MERS-CoV polymerase complexes.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; Coronavirus; Coronavirus Infections; Exonucleases; Humans; Pandemics; RNA-Dependent RNA Polymerase; Virus Replication
PubMed: 32277065
DOI: 10.1074/jbc.H120.013397 -
Cell Reports Sep 2023In ribosome-associated quality control (RQC), nascent polypeptides produced by interrupted translation are modified with C-terminal polyalanine tails ("Ala-tails") that...
In ribosome-associated quality control (RQC), nascent polypeptides produced by interrupted translation are modified with C-terminal polyalanine tails ("Ala-tails") that function outside ribosomes to induce ubiquitylation by E3 ligases Pirh2 (p53-induced RING-H2 domain-containing) or CRL2 (Cullin-2 RING ligase2)-KLHDC10. Here, we investigate the molecular basis of Ala-tail function using biochemical and in silico approaches. We show that Pirh2 and KLHDC10 directly bind to Ala-tails and that structural predictions identify candidate Ala-tail-binding sites, which we experimentally validate. The degron-binding pockets and specific pocket residues implicated in Ala-tail recognition are conserved among Pirh2 and KLHDC10 homologs, suggesting that an important function of these ligases across eukaryotes is in targeting Ala-tailed substrates. Moreover, we establish that the two Ala-tail-binding pockets have convergently evolved, either from an ancient module of bacterial provenance (Pirh2) or via tinkering of a widespread C-degron-recognition element (KLHDC10). These results shed light on the recognition of a simple degron sequence and the evolution of Ala-tail proteolytic signaling.
Topics: Humans; Alanine; Binding Sites; Proteolysis; Ubiquitin-Protein Ligases; Ubiquitination; Carrier Proteins
PubMed: 37676773
DOI: 10.1016/j.celrep.2023.113100 -
Vaccine Aug 2019Rabies virus remains an important burden of disease claiming an estimated 60,000 lives each year, mainly children, and having a huge economical and societal cost.... (Review)
Review
Rabies virus remains an important burden of disease claiming an estimated 60,000 lives each year, mainly children, and having a huge economical and societal cost. Post-exposure prophylaxis (PEP) is highly effective, however in patients that present with neurological symptoms the case-fatality ratio is extremely high (>99%). During the last decades several attempts to identify potent and effective antivirals were made. Only a few of these demonstrated improvement in clinical signs in animal studies and none of the trials in humans showed significant efficacy. Here we explore novel opportunities to identify more potent anti-rabies molecules. In particular important progress has been made on antivirals against other Mononegavirales (paramyxoviruses, filoviruses) which should be an impetus to test and optimize these molecules towards anti-rabies virus therapies. Effective rabies antivirals for therapeutic use need to be molecules that can be dosed into the cerebrospinal fluid and that rapidly and potently block ongoing virus replication and as such stop the further spread of the virus. Antivirals for prophylactic use can also be envisaged and these should be able to prevent infection of peripheral nerve cells and should have the potential to replace the current anti-rabies immunoglobulins that are used in PEP.
Topics: Adenine; Adenosine; Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Drug Repositioning; Humans; Post-Exposure Prophylaxis; Pyrazines; Pyrrolidines; Rabies; Rabies virus
PubMed: 29279280
DOI: 10.1016/j.vaccine.2017.12.051 -
European Journal of Internal Medicine Aug 2022The clinical progression of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to critical illness is associated with a systemic and uncontrolled... (Review)
Review
The clinical progression of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to critical illness is associated with a systemic and uncontrolled inflammatory response of the innate and adaptive immunity with the release of a plethora of proinflammatory cytokines termed "cytokine storm". In the absence of an effective treatment, many off-label agents from the armamentarium of rheumatology are used. Here, from the perspective of a rheumatologist, we will discuss the current therapeutic strategies in critically ill patients with SARS-CoV-2 pneumonia. Thus, we will discuss the agents that aim to target viral entry and its replication into the host cell and those focusing and targeting the inflammatory response. In this setting, many agents have been used with promising results but, not all have been approved by the International Authorities and Institutions. In the first step (viral entry), SARS-CoV-2 monoclonal antibodies and remdesivir have been approved to be used and, in the second step, corticosteroids along with interleukin-6 inhibitors, or Janus Kinase inhibitors are currently used.
Topics: Adenosine Monophosphate; Adrenal Cortex Hormones; Alanine; Antibodies, Monoclonal; Critical Illness; Cytokine Release Syndrome; Cytokines; Humans; Rheumatology; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35610165
DOI: 10.1016/j.ejim.2022.05.014