Affinity of the antiviral enantiomers of oxathiolane cytosine nucleosides for human 2'-deoxycytidine kinase

The two enantiomers of 2',3'-dideoxy-3'-thiacytidine (BCH-189) and their 5-fluoro analogs (FTC) were found to be good substrates for human 2'-deoxycytidine kinase with Km values in the 5.7 to 42.1 [mu]M range. The affinity of the (-)-enantiomers was greater than that of the (+)-compounds. These results may explain the greater in vitro antiviral potency against human immunodeficiency virus and hepatitis B virus of the (-)-enantiomers when compared to their (+)-counterparts. The (+)- and (-)-enantiomers of FTC and BCH-189 are the first nucleoside analogs for which we have observed lower apparent kinetic constants for this enzyme in the presence of ATP compared to UTP.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30848/1/0000510.pd

Calculated conformer energies for organic molecules with multiple polar functionalities are method dependent: Taxol (case study)

BACKGROUND: Molecular mechanics (MM) and quantum chemical (QM) calculations are widely applied and powerful tools for the stereochemical and conformational investigations of molecules. The same methods have been extensively used to probe the conformational profile of Taxol (Figure 1) both in solution and at the β-tubulin protein binding site. RESULTS: In the present work, the relative energies of seven conformations of Taxol derived from NMR and X-ray analyses were compared with a set of widely used force fields and semiempirical MO methods coupled to a continuum solvent treatment. The procedures not only diverge significantly in their assessment of relative conformational energies, but none of them provide satisfactory agreement with experiment. CONCLUSIONS: For Taxol, molecular mechanics and semiempirical QM methods are unable to provide a consistent energetic ranking of side-chain conformations. For similar highly polar organic structures, "energy-free" conformational search methods are advised

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Expanding the toolbox of metabolically stable lipid prodrug strategies

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside and nucleotide therapeutics, small context-dependent amendments to these popular prodrug strategies can drive dramatic improvements in pharmacokinetic (PK) profiles. Herein we offer a brief overview of current prodrug strategies, as well as a case study involving the fine-tuning of lipid prodrugs of acyclic nucleoside phosphonate tenofovir (TFV), an approved nucleotide HIV reverse transcriptase inhibitor (NtRTI) and the cornerstone of combination antiretroviral therapy (cART). Installation of novel lipid terminal motifs significantly reduced fatty acid hepatic ω-oxidation while maintaining potent antiviral activity. This work contributes important insights to the expanding repertoire of lipid prodrug strategies in general, but particularly for the delivery and distribution of acyclic nucleoside phosphonates

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

North-South Collaborations to Promote Health Innovation in Africa

The significant interest in and reference to regional innovation networks for health capacity building within international and regional public health and development strategies has not been matched with the operational support they need. There is little guidance about how to create and sustain such networks and about how north-south collaborations can contribute to their success. This Article describes a model for building African health capacity through regional health innovation networks that focuses on the complete pathway from idea to commercialization of health technologies, and it suggests guidelines for effective north-south collaborations to support this approach. In doing so, the Article highlights the importance of local legal and business capacity building as part of a product-focused, network-based health innovation strategy

North-South Collaborations to Promote Health Innovation in Africa

The significant interest in and reference to regional innovation networks for health capacity building within international and regional public health and development strategies has not been matched with the operational support they need. There is little guidance about how to create and sustain such networks and about how north-south collaborations can contribute to their success. This Article describes a model for building African health capacity through regional health innovation networks that focuses on the complete pathway from idea to commercialization of health technologies, and it suggests guidelines for effective north-south collaborations to support this approach. In doing so, the Article highlights the importance of local legal and business capacity building as part of a product-focused, network-based health innovation strategy

Organic syntheses: reaction guide

xiv+854hlm.;24c