Highlights d ATAC-seq accessibility at sperm and oocyte promoters is maintained in the embryo d Sperm enhancers containing transcription factors are conserved in mammals d Accessible sperm enhancers are also open in oocytes and preimplantation embryos d Interactions mediated by FoxA1 and CTCF and cohesin persist from gametes to embryos

Transgenerational inheritance requires mechanisms by which epigenetic information is transferred via gametes. Canonical thought holds that mammalian sperm chromatin would be incapable of carrying epigenetic information as post-translational modifications of histones because of their replacement with protamine proteins. Furthermore, compaction of the sperm genome would hinder DNA accessibility of proteins involved in transcriptional regulation and genome architecture. In this Minireview, we delineate the paternal chromatin remodeling events during spermatogenesis and fertilization. Sperm chromatin is epigenetically modified at various time points throughout its development. This allows for the addition of environment-specific modifications that can be passed from parents to offspring.

5-Fluorouracil and 5-fluorouracil-based prodrugs have been used clinically for decades to treat cancer. Their anticancer effects are most prominently ascribed to inhibition of thymidylate synthase (TS) by metabolite 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP). However, 5-fluorouracil and FdUMP are subject to numerous unfavorable metabolic events that can drive undesired systemic toxicity. Our previous research on antiviral nucleotides suggested that substitution at the nucleoside 5′-carbon imposes conformational restrictions on the corresponding nucleoside monophosphates, rendering them poor substrates for productive intracellular conversion to viral polymerase-inhibiting triphosphate metabolites. Accordingly, we hypothesized that 5′-substituted analogs of FdUMP, which is uniquely active at the monophosphate stage, would inhibit TS while preventing undesirable metabolism. Free energy perturbation-derived relative binding energy calculations suggested that 5′(R)-CH3 and 5′(S)-CF3 FdUMP analogs would maintain TS potency. Herein, we report our computational design strategy, synthesis of 5′-substituted FdUMP analogs, and pharmacological assessment of TS inhibitory activity.

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.

An analysis of nucleoside active metabolite potencies against Hepatitis C virus (HCV) versus their parent ground state energetic conformational bias as calculated by Density Functional Theory suggested that nucleotides with a small difference between their antipodal energies are more likely to have potent antiviral activity compared to those with larger energetic differences. This energetic conformational bias was thought to be manipulated with substitutions along the ribofuranose ring. From 2’-C-methyluridine, a representative nucleoside with fair anti-HCV activity, two C3’ modifications in particular (ethyne and methyl) showed contrasting antipodal biases relative to each other while originating from a common synthetic intermediate, allowing a test of reasonable extremes of the computational model with a divergent 9-step synthesis. Antiviral activity of the compounds contradicted that suggested by the model, indicating a need for further refinement with additional biostructural considerations.