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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 -
The Lancet. Infectious Diseases Feb 2022
Topics: Adenosine Monophosphate; Alanine; Humans
PubMed: 34534513
DOI: 10.1016/S1473-3099(21)00559-4 -
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 -
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 -
Revista Espanola de Quimioterapia :... Apr 2022
Topics: Adenosine Monophosphate; Alanine; Humans
PubMed: 35118854
DOI: 10.37201/req/147.2021 -
Biochemical Pharmacology Aug 2018Tanovea® (first named GS-9219, then VDC-1101, generic name: rabacfosadine) is a pro-prodrug or "double" prodrug of PMEG [9-(2-phosphonylmethoxyethyl)guanine], which has... (Review)
Review
Tanovea® (first named GS-9219, then VDC-1101, generic name: rabacfosadine) is a pro-prodrug or "double" prodrug of PMEG [9-(2-phosphonylmethoxyethyl)guanine], which has been conditionally approved by the US FDA (Food and Drug Administration) for the treatment of lymphoma in dogs. Tanovea has been demonstrated to be effective against non-Hodgkin's lymphoma (NHL) in dogs, as well as canine cutaneous T-cell lymphoma, spontaneous canine multiple myeloma, naïve canine multicentric lymphoma and relapsed canine B-cell lymphoma. As a double prodrug of PMEG, GS-9219 is first converted intracellularly by hydrolysis to cPr-PMEDAP, then deaminated to PMEG, which is then phosphorylated twice to its active metabolite PMEGpp, acting at the level of the cellular DNA polymerases.
Topics: Alanine; Animals; Antineoplastic Agents; Dogs; Lymphoma; Prodrugs; Purines; Treatment Outcome
PubMed: 29778492
DOI: 10.1016/j.bcp.2018.05.010 -
The FEBS Journal Jun 2023Alanine racemases (ALRs) are essential for d-alanine (d-Ala) production in bacteria, and many ALRs have a conserved carbamylated lysine residue in the active site....
Alanine racemases (ALRs) are essential for d-alanine (d-Ala) production in bacteria, and many ALRs have a conserved carbamylated lysine residue in the active site. Although short-chain carboxylates inhibit ALRs harbouring this lysine residue as substrate analogues, in an ALR variant with an alanine residue at this position, carboxylates behave as activators; however, this activation mechanism remains unclear. Here, we performed kinetic and structural analyses of U1ALR, an ALR from Latilactobacillus sakei UONUMA harbouring a glycine residue (Gly134) in the site of the carbamylated lysine residue. U1ALR was activated by various carboxylates and also by a G134K mutation, both of which caused a significant decrease in K , indicating an increase in substrate affinity. The U1ALR crystal structure revealed the presence of an acetate molecule bound in a position and at an orientation resembling the conformation of the carbamylated lysine side chain observed in the structures of other ALRs. These results suggest a regulatory mechanism for U1ALR activity involving two carboxylate-binding sites: one with high affinity near Gly134, where an acetate molecule is observed in the crystal structure and carboxylate binding results in enzyme activation; the other is the substrate-binding site, where carboxylate binding inhibits enzyme activity. Furthermore, we observed no carboxylate/G134K-mediated activation in the presence of d-Ala at high concentrations, implying that d-Ala also exhibits low-affinity binding in the first carboxylate-binding site and prevents carboxylate/G134K-induced activation. Such regulation of enzyme activity by carboxylates and d-Ala may be ubiquitous in many ALRs from lactic acid bacteria sharing the same sequence characteristics.
Topics: Alanine Racemase; Alanine; Lysine; Binding Sites; Catalytic Domain; Carboxylic Acids; Kinetics
PubMed: 36732053
DOI: 10.1111/febs.16745 -
Clinical and Translational Science Apr 2022
Topics: Adenosine Monophosphate; Alanine; Cardiovascular Diseases; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacovigilance; Product Surveillance, Postmarketing
PubMed: 35303401
DOI: 10.1111/cts.13261 -
The Lancet. Infectious Diseases Dec 2021
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Humans; Randomized Controlled Trials as Topic; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 34838222
DOI: 10.1016/S1473-3099(21)00695-2 -
CMAJ : Canadian Medical Association... Jan 2021
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Chemical and Drug Induced Liver Injury; Critical Care; Drug Hypersensitivity; Humans; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33408097
DOI: 10.1503/cmaj.202505