n6-(4-hydroxybenzyl)adenine-riboside and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Aging is a natural human process. It is uniquely individual, taking into account experiences, lifestyle habits and environmental factors. However, many disorders and syndromes, such as osteoporosis, neurodegenerative disorders, cognitive decline etc., often come with aging. The present study was designed to investigate the possible anti-aging effect of

Topics: Adenosine; Aging; Animals; Cellular Senescence; Cognitive Dysfunction; Disease Models, Animal; Galactose; Gastrodia; Hippocampus; Humans; Male; Mice; Neurogenesis; Neurons; Oxidative Stress; Reactive Oxygen Species

Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed.. Here, we report a novel dual-function compound, N(6)-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A(2A)R and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2A)R and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2A)R knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2A)R in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD.. The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.

Topics: Adenosine; Animals; Disease Models, Animal; Drug Design; Drugs, Chinese Herbal; Equilibrative Nucleoside Transporter 1; Female; Humans; Huntington Disease; Male; Mice; Mice, Knockout; Models, Molecular; PC12 Cells; Peptides; Plant Extracts; Rats; Receptor, Adenosine A2A; Trinucleotide Repeat Expansion

Serum deprivation-induced neuronal-like PC12 cell apoptosis was used as an ischemic/hypoxic model to screen neuroprotective compounds from the rhizomes of Gastrodia elata, a traditional Chinese medicine. Two active compounds, bis(4-hydroxybenzyl)sulfide (1) and N6-(4-hydroxybenzyl)adenine riboside (2), together with 15 known compounds were obtained from the active fraction. Compound 2 was further elucidated by chemical synthesis. Compounds 1 and 2 potently prevented PC12 cell apoptosis in concentration-dependent manners with EC50 values of 7.20 microM and 3.7 x 10-8 M, respectively, and IC50 values of 42.90 microM (Ki 24.10 microM) and 4.660 microM (Ki 2.620 microM), respectively, in an adenosine A2A receptor binding assay.

Topics: Adenosine; Animals; Apoptosis; Disease Models, Animal; Drugs, Chinese Herbal; Gastrodia; Molecular Structure; Neuroprotective Agents; PC12 Cells; Plants, Medicinal; Rats; Receptor, Adenosine A2A; Serum; Sulfides