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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 -
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 -
Biological & Pharmaceutical Bulletin Sep 2005Aquatic crustaceans and some bivalve mollusks contain a large amount of free D-alanine (up to 100 mumol/g wet wt.) in their tissues. Under high salinity stress,... (Review)
Review
Aquatic crustaceans and some bivalve mollusks contain a large amount of free D-alanine (up to 100 mumol/g wet wt.) in their tissues. Under high salinity stress, crustaceans and bivalve mollusks largely accumulate D- and L-alanine irrespective of species examined, together with L-glutamine, L-proline, and glycine of which increases are species dependent. These data indicate that D-alanine is one of the major compatible osmolytes responsible for the intracellular isosmotic regulation in the tissues of crustaceans and bivalves. Alanine racemase has been proven to catalyze the interconversion of D- and L-alanine in these invertebrates. The enzyme has been isolated to homogeneity from the muscle of black tiger prawn Penaeus monodon and its cDNA has been cloned from the muscle and hepatopancreas of kuruma prawn Penaeus japonicus for the first time in eukaryotes other than yeast. Several fish species fed on crustaceans and mollusks contain D-amino acid and D-aspartate oxidases that catalyze the decomposition of D-amino acids. A cDNA of D-amino acid oxidase has been cloned from the hepatopancreas of omnivorous common carp Cyprinus carpio. During oral administration of free D-alanine to carp, the activity and mRNA of D-amino acid oxidase increased rapidly in hepatopancreas and the increases were highest in intestine followed by hepatopancreas and kidney. These data suggest that D-amino acid oxidase is inducible in carp and an important enzyme responsible for the efficient utilization of carbon skeleton of D-alanine in their feeds.
Topics: Alanine; Animals; Fishes; Hypoxia; Invertebrates; Osmolar Concentration
PubMed: 16141518
DOI: 10.1248/bpb.28.1571 -
Journal of Veterinary Internal Medicine Jan 2022Rabacfosadine (RAB, Tanovea-CA1) is a novel chemotherapy agent conditionally approved for the treatment of lymphoma in dogs.
BACKGROUND
Rabacfosadine (RAB, Tanovea-CA1) is a novel chemotherapy agent conditionally approved for the treatment of lymphoma in dogs.
HYPOTHESIS/OBJECTIVES
To determine the efficacy and safety of RAB in dogs with lymphoma.
ANIMALS
One hundred and fifty-eight client-owned dogs with naïve or relapsed multicentric lymphoma were prospectively enrolled from January to October 2019.
METHODS
Dogs were randomized to receive RAB or placebo at a 3 : 1 ratio. Treatment was given every 21 days for up to 5 treatments. Study endpoints included progression-free survival (PFS), overall response rate (ORR) at a given visit, best overall response rate (BORR), and percent progression free 1 month after treatment completion. Safety data were also collected.
RESULTS
The median PFS was significantly longer in the RAB group compared to placebo (82 vs 21 days; P < .0001, HR 6.265 [95% CI 3.947-9.945]). The BORR for RAB-treated dogs was 73.2% (50.9% complete response [CR], 22.3% partial response [PR]) and 5.6% (0% CR, 5.6% PR) for placebo-treated dogs (P < .0001). One month after the last treatment, 37 RAB-treated dogs (33%) were progression free compared with no placebo-treated dogs (P < .0001). The most common adverse events observed in the RAB group were diarrhea (87.5%), decreased appetite (68.3%), and vomiting (68.3%) and were generally low grade and reversible. Serious adverse events were reported in 24 RAB-treated (20%) and 5 placebo-treated dogs (13%).
CONCLUSIONS AND CLINICAL IMPORTANCE
Rabacfosadine demonstrated statistically significant antitumor efficacy in dogs with lymphoma when administered every 21 days for up to 5 treatments as compared to placebo.
Topics: Alanine; Animals; Antineoplastic Combined Chemotherapy Protocols; Dog Diseases; Dogs; Lymphoma; Purines; Treatment Outcome
PubMed: 34952995
DOI: 10.1111/jvim.16341 -
The Journal of Antimicrobial... Dec 2021Mounting evidence suggests that pregnant people have an elevated risk of severe COVID-19-related complications compared with their non-pregnant counterparts,... (Review)
Review
Mounting evidence suggests that pregnant people have an elevated risk of severe COVID-19-related complications compared with their non-pregnant counterparts, underscoring the need for effective prevention and treatment strategies. However, despite progress in innovative and flexible trial designs during the COVID-19 pandemic, regressive policies excluding pregnant and breastfeeding people from biomedical research persist. Remdesivir, a broad-spectrum antiviral, was the first drug licensed for the treatment of COVID-19, based on data showing it reduced the time to recovery in hospitalized patients. Pregnant and breastfeeding people were specifically excluded from all clinical trials of remdesivir in COVID-19, but data are accumulating from post-marketing registries, compassionate use programmes and case series/reports. In this review we synthesize these data and highlight key knowledge gaps to help inform clinical decision-making about its use in pregnancy and lactation.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Breast Feeding; Female; Humans; Lactation; Pandemics; Pregnancy; Pregnancy Complications, Infectious; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34427297
DOI: 10.1093/jac/dkab311 -
European Review For Medical and... Jan 2021List the clinical data of the role of remdesivir in COVID-19, and try to make an objective evaluation and analyze its feasibility. (Review)
Review
OBJECTIVE
List the clinical data of the role of remdesivir in COVID-19, and try to make an objective evaluation and analyze its feasibility.
MATERIALS AND METHODS
The keywords of "remdesivir", "COVID-19" and "SARS-CoV-2" were systematically searched in PubMed and Web of Science. After removing the repetitions, we summarize articles, letters, and comments on remdesivir in the treatment of COVID-19.
RESULTS
In this review, we summarize clinical case of using remdesivir in the treatment of COVID-19, analyzed the final treatment results, and judged whether the drug was effective for the treatment of COVID-19. Also, attention was paid to the side effects of the drug.
CONCLUSIONS
According to the clinical results, it was found that remdesivir was effective in the treatment of COVID-19. The drug has side effects, but the symptoms were mild and disappeared immediately after discontinuation of medication.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Humans; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33506946
DOI: 10.26355/eurrev_202101_24426 -
Biomedicine & Pharmacotherapy =... Mar 2022Coronavirus disease 2019 (COVID-19) represents an unmet clinical need, due to a high mortality rate, rapid mutation rate in the virus, increased chances of reinfection,... (Comparative Study)
Comparative Study Review
Coronavirus disease 2019 (COVID-19) represents an unmet clinical need, due to a high mortality rate, rapid mutation rate in the virus, increased chances of reinfection, lack of effectiveness of repurposed drugs and economic damage. COVID-19 pandemic has created an urgent need for effective molecules. Clinically proven efficacy and safety profiles have made favipiravir (FVP) and remdesivir (RDV) promising therapeutic options for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Even though both are prodrug molecules with an antiviral role based on a similar mechanism of action, differences in pharmacological, pharmacokinetic and pharmacotoxicological mechanisms have been identified. The present study aims to provide a comprehensive comparative assessment of FVP and RDV against SARS-CoV-2 infections, by centralizing medical data provided by significant literature and authorized clinical trials, focusing on the importance of a better understanding of the interactions between drug molecules and infectious agents in order to improve the global management of COVID-19 patients and to reduce the risk of antiviral resistance.
Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Humans; Pyrazines; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35131656
DOI: 10.1016/j.biopha.2022.112700 -
Journal of Medicinal Chemistry Aug 2014Protein structure underlies essential biological processes and provides a blueprint for molecular mimicry that drives drug discovery. Although small molecules represent... (Review)
Review
Protein structure underlies essential biological processes and provides a blueprint for molecular mimicry that drives drug discovery. Although small molecules represent the lion's share of agents that target proteins for therapeutic benefit, there remains no substitute for the natural properties of proteins and their peptide subunits in the majority of biological contexts. The peptide α-helix represents a common structural motif that mediates communication between signaling proteins. Because peptides can lose their shape when taken out of context, developing chemical interventions to stabilize their bioactive structure remains an active area of research. The all-hydrocarbon staple has emerged as one such solution, conferring α-helical structure, protease resistance, cellular penetrance, and biological activity upon successful incorporation of a series of design and application principles. Here, we describe our more than decade-long experience in developing stapled peptides as biomedical research tools and prototype therapeutics, highlighting lessons learned, pitfalls to avoid, and keys to success.
Topics: Alanine; Animals; Biomedical Research; Cross-Linking Reagents; Humans; Hydrocarbons; Peptide Fragments; Peptides; Protein Structure, Secondary; Protein Unfolding; Proteolysis; Proto-Oncogene Proteins; Structure-Activity Relationship
PubMed: 24601557
DOI: 10.1021/jm4011675 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2018Lanthionine (Lan), a non-proteinogenic natural amino acid, is an essential component of peptidoglycan found in the cell wall of Fusobacterium species. Lan and... (Review)
Review
Lanthionine (Lan), a non-proteinogenic natural amino acid, is an essential component of peptidoglycan found in the cell wall of Fusobacterium species. Lan and β-methyllanthionine are also key constituents in lantibiotics, a prevalent class of peptide antibiotics. The development of those new antibacterial drugs with enhanced properties is the focus of recent research. Since multiple isomers of Lan are possible, a regio- and diastereoselective synthesis is challenging. This comprehensive review summarizes the known chemical syntheses of lanthionine from various precursors (e.g., β-chloroalanine, cystine, dehydroalanine, β-iodoalanine, aziridine, serine lactone, sulfamidate) since 1941. Methods for preparation of unprotected, protected, orthogonally protected, and mutually orthogonally protected lanthionine with relevant experimental details and perspectives on their usefulness are provided. The potential of these Lan derivatives is illustrated by one recent application.
Topics: Alanine; Chemistry Techniques, Analytical; Molecular Structure; Stereoisomerism; Sulfides
PubMed: 29714402
DOI: 10.1002/chem.201801115 -
The Lancet. Infectious Diseases Feb 2022
Topics: Adenosine Monophosphate; Alanine; Humans
PubMed: 34534513
DOI: 10.1016/S1473-3099(21)00559-4