Nucleic acid medicines are a highly attractive modality that act in a sequence-specific manner on target molecules. To date, 21 such products have been approved by the Food and Drug Administration. However, the development of nucleic acid medicines continues to face various challenges, including tissue and cell targeting as well as intracellular delivery.
View Article and Find Full Text PDFSodium-glucose cotransporter 2 (SGLT2) inhibitors are clinically available to control blood glucose levels in diabetic patients via an insulin-independent mechanism. It was found that some carbasugar analogs of known SGLT2 inhibitors exert a high inhibiting ability toward SGLT2 and have a prolonged blood glucose lowering effect. In this study, we designed new candidates of carbasugar SGLT2 inhibitor that can be synthesized using copper-catalyzed azide-alkyne cycloaddition (CuAAC) into an aromatic ring, which is a part of the pharmacophore at the final stage in the synthetic protocol for the easier discovery of superior SGLT2 inhibitors.
View Article and Find Full Text PDFThe spread of SARS-CoV-2, the causative agent for COVID-19, has led to a global and deadly pandemic. To date, few drugs have been approved for treating SARS-CoV-2 infections. In this study, a structure-based approach was adopted using the SARS-CoV-2 main protease (M) and a carefully selected dataset of 37,060 compounds comprising M and antiviral protein-specific libraries.
View Article and Find Full Text PDFFollowing the recent emergence of SARS-CoV-2 or coronavirus disease 2019 (COVID-19), drug discovery and vaccine design to combat this fatal infection are critical. In this study, an essential enzyme in the SARS-CoV-2 replication machinery, RNA-dependent RNA polymerase (RDRP), is targeted in a virtual screening assay using a set of 1,664 FDA-approved drugs, including sets of botanical and synthetic derivatives. A set of 22 drugs showed a high docking score of >-7.
View Article and Find Full Text PDFWe found that sulfisomidine, a sulfonamide antibiotic, potently binds to the Piwi/Argonaute/Zwille (PAZ) domain of human Argonaute protein 2 and inhibits RNA interference (RNAi). To elucidate the effect on RNAi of strong affinity of the 3'-ends in small interfering RNA (siRNA) to the PAZ domain, chemically modified siRNAs bearing sulfisomidine at the 3'-end were synthesized.
View Article and Find Full Text PDFThe papain-like protease (PL ) is an important enzyme for coronavirus polyprotein processing, as well as for virus-host immune suppression. Previous studies reveal that a molecular analysis of PL indicates the catalytic activity of viral PL and its interactions with ubiquitin. By using sequence comparisons, molecular models, and protein-protein interaction maps, PL was compared in the three recorded fatal CoV epidemics, which involved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome CoV (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV).
View Article and Find Full Text PDFThis study was conducted to evaluate the pharmacokinetics of cefquinome in camel calves after a single intramuscular injection in a dose of 2 mg/kg body weight (kg b. w.).
View Article and Find Full Text PDFNucleosides Nucleotides Nucleic Acids
September 2020
Deuterated drugs are valuable in the fields of drug discovery and medicinal chemistry. 2',3',5',5″-tetradeuterated uridine derivatives were synthesised from 2,3,5,5'-selectively tetradeuterated ribose using Sajiki's H-D exchanged Ru/C-H2-D2O-NaOH system and silyl-Hilbert-Johnson methods. The total deuterium content of the tetradeuterated uridines was over 92% using either basic or acidic reaction conditions.
View Article and Find Full Text PDFStimuli-controlled structural transitions of nucleic acids have received growing attentions owing to their potential applications in the fields of chemical and synthetic biology. Here, we describe the development of reduction-responsive deoxyribonucleic acid (DNA) duplexes, in which guanine rings bearing a reduction-responsive cleavable nitrobenzyl (NB) group at the position (G) are introduced at defined positions. We demonstrate that the artificial NB group can be removed in response to reduction stimulus without the dissociation of the intermolecular duplex structure, which comprises a G-quadruplex forming nucleic acid strand with one G and its complementary sequence with one mismatch pair.
View Article and Find Full Text PDFMicroRNAs (miRNA) are small, noncoding RNA molecules consisting of 18 to 25 nucleotides. Malignant melanomas (MMs) are one of the most common malignancies in both dogs and humans. We previously reported that chemically modified synthetic miRNA-205 (miR-205BP/S3) inhibits melanoma growth in vitro and in vivo.
View Article and Find Full Text PDFPlasmodium falciparum thymidylate kinase (PfTMK) showed structural and catalytic distinctions from the host enzyme rendering it a hopeful antiprotozoal drug target. Despite the comprehensive enzymologic, structural, inhibitory and chemical synthesis approaches targeting this enzyme, the elucidation of the exact mechanism underlying the recognition of the atypical purine substrates remains to be determined. In this study, molecular dynamics (MD) simulation of a broad range of substrates and inhibitors as well as the inhibitory properties of deoxyguanosine (dG) derivatives were used to assess the PfTMK substructure molecular rearrangements.
View Article and Find Full Text PDFThe 2'-5'-oligoadenylate synthetase (OAS)/RNase L pathway is an innate immune system that protects hosts against pathogenic viruses and bacteria through cleavage of exogenous single-stranded RNA; however, this system's selective targeting mechanism remains unclear. Here, we identified an mRNA quality control factor Dom34 as a novel restriction factor for a positive-sense single-stranded RNA virus. Downregulation of Dom34 and RNase L increases viral replication, as well as half-life of the viral RNA.
View Article and Find Full Text PDFBioorg Med Chem Lett
October 2018
Glucosamino nucleic acids (GANAs) bearing a β-N-glycoside bond between carbon 1 of the glucosamine and the nucleobase nitrogen were synthesized and incorporated into oligonucleotides (4',6'-GANA and 3',6'-GANA). The thermal stability of oligonucleotide duplexes containing the GANA zwitterionic nucleotides was also investigated.
View Article and Find Full Text PDFDespite considerable research on K-Ras inhibitors, none had been established until now. We synthesized nuclease-resistant synthetic miR-143 (miR-143#12), which strongly silenced K-Ras, its effector signal molecules AKT and ERK, and the K-Ras activator Sos1. We examined the anti-proliferative effect of miR-143#12 and the mechanism in human colon cancer DLD-1 cell (G13D) and other cell types harboring K-Ras mutations.
View Article and Find Full Text PDFChemically modified siRNAs containing 2-O-benzyl-1-deoxy-d-ribofuranose (R) in their 3'-overhang region were significantly more resistant towards serum nucleases than siRNAs possessing the natural nucleoside in this region. The knockdown efficacies and binding affinities of these modified siRNAs to the recombinant human Argonaute protein 2 (hAgo2) PAZ domain were comparable with that of siRNA with a thymidine dimer at the 3'-end.
View Article and Find Full Text PDFRNA interference (RNAi) constitutes a major target in drug discovery. Recently, we reported that the Argonaute protein 2 (Ago2) PAZ domain selectively binds with all ribonucleotides except adenine and poorly recognizes deoxyribonucleotides. The binding properties of the PAZ domain with polynucleotides and the molecular mechanisms of substrates' selectivity remains unclear.
View Article and Find Full Text PDFThe formation of 1,4-disubstituted 1,2,3-triazoles through copper-catalyzed azide-alkyne cycloaddition (CuAAC) in oligonucleotides bearing 1-deoxy-1-ethynyl-β-d-ribofuranose (R) can have a positive impact on the stability of oligonucleotide duplexes and stem-loop structures.
View Article and Find Full Text PDFBackground: is one of major causes of foodborne outbreaks globally. This study was conducted to estimate the prevalence, typing and antibiotic susceptibilities of serovars isolated from 41 broiler chicken farms located in Kafr El-Sheikh Province in Northern Egypt during 2014-2015. The clinical signs and mortalities were observed.
View Article and Find Full Text PDFPLEKHG2/FLJ00018 is a Gβγ-dependent guanine nucleotide exchange factor for the small GTPases Rac and Cdc42 and has been shown to mediate the signaling pathways leading to actin cytoskeleton reorganization. Here we showed that the zinc finger domain-containing protein four-and-a-half LIM domains 1 (FHL1) acts as a novel interaction partner of PLEKHG2 by the yeast two-hybrid system. Among the isoforms of FHL1 (i.
View Article and Find Full Text PDFCamels are raised in harsh desert environment for hundreds of years ago. By modernization of live and the growing industrial revolution in camels rearing areas, camels are exposed to considerable amount of chemicals, industrial waste, environmental pollutions and drugs. Furthermore, camels have unique gene evolution of some genes to withstand living in harsh environments.
View Article and Find Full Text PDFRNase L is activated by 2',5'-oligoadenylates (2-5A) at subnanomolar levels to cleave single-stranded RNA. We previously reported the hypothesis that the introduction of an 8-methyladenosine residue at the 2'-terminus of the 2-5A tetramer shifts the 2-5A binding site of RNase L. In this study, we synthesized various 5'-modified 2-5A analogs with 8-methyladenosine at the 2'-terminus.
View Article and Find Full Text PDFStimulus-responsive biomolecules are attractive targets to understand biomolecule behaviour as well as to explore their therapeutic and diagnostic applications. We demonstrate that a reduction-responsive cleavable group (chemically caged unit) introduced into the guanine ring enables modulation of the secondary structure transition of an oligonucleotide in a reduction-responsive and traceless manner leaving the unmodified oligonucleotide of interest. This simple but robust strategy could yield a variety of stimuli-responsive oligonucleotides.
View Article and Find Full Text PDFNucleosides Nucleotides Nucleic Acids
December 2016
We developed a practical and reliable method for synthesizing an abasic deoxyribonucleoside, 1,2-dideoxy-d-ribofuranose (dR(H)) via elimination of nucleobase from thymidine. To synthesize oligonucleotides bearing dR(H) by the standard phosphoramidite solid-phase method, dR(H) was converted to the corresponding phosphoramidite derivative and linked to a solid support (controlled pore glass resin). Chemically modified small interfering RNAs (siRNAs) possessing dR(H) at their 3'-overhang regions were synthesized.
View Article and Find Full Text PDFS-adenosyl-L-homocysteine hydrolase (SAH hydrolase or SAHH) is a highly conserved enzyme that catalyses the reversible hydrolysis of SAH to L-homocysteine (HCY) and adenosine (ADO). High-resolution crystal structures have been reported for bacterial and plant SAHHs, but not mammalian SAHHs. Here, we report the first high-resolution crystal structure of mammalian SAHH (mouse SAHH) in complex with a reaction product (ADO) and with two reaction intermediate analogues-3'-keto-aristeromycin (3KA) and noraristeromycin (NRN)-at resolutions of 1.
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