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Inhibition of viral reverse transcriptases and mammalian DNA polymerases by unnatural nucleoside analogs is a proven approach in antiviral and anticancer therapy, respectively. The majority of current nucleoside drugs retain the canonical nucleobase structure, which is fused to an unnatural sugar. In the present work, a series of novel pyrrolidine-functionalized purine and pyrimidine nucleosides was prepared via PyBOP-catalyzed SNAr addition-elimination reactions of commercial halogenated precursors and tested for their antiviral and anticancer activity. The newly synthesized nucleoside analogs showed limited biological activity, probably as a result of their poor cellular uptake and their inefficient bioactivation to the corresponding nucleoside monophosphates. A phosphoramidate prodrug had an improved cell permeability and was metabolized to the nucleoside monophosphate form in human cells, as revealed by HPLC-MS/MS analyses.

Taking advantage of the uniquely constricted active site of SARS-CoV-2 Nsp14 methyltransferase, we have designed bisubstrate inhibitors interacting with the SAM and RNA substrate binding pockets. Our efforts have led to nanomolar inhibitors including compounds

Twenty-nine nucleoside analogues have been synthesized and evaluated in a cell based assay for their ability to activate the human Stimulator of Interferon Genes (hSTING), a key protein of the innate immune defense. Some 6-O-alkyl nucleoside analogues activate hSTING without associated cytotoxicity. SAR and combination studies were performed to decipher possible activation mechanism. The described nucleoside hSTING activators represent first-in-class modulators of the innate immune defense; a highly relevant target for antiviral, antibacterial, anticancer or Alzheimer's disease treatments and may present advantages over other types of hSTING activators.

Excessive exposure to sunlight is primarily implicated in ultraviolet (UV) induced skin cancers worldwide. Direct absorption of UV radiation by DNA leads to the formation of cyclobutane pyrimidine dimers (CPDs) resulting in DNA damage. The molecular mechanisms involved in the mutagenicity of CPDs are well established. Photoprotection of the skin from the detrimental effects of UV is essential in preventing skin damage. A variety of formulations, which essentially contain UV filters have been used as photoprotective agents of the skin. These comprise aromatic and inorganic molecules, whose mechanism of action involves either absorption, reflection, or scattering of UV radiation. However, the downstream photoproducts of some of these molecules have undesirable characteristics which compromise their utility. A biomimetic approach involving structural analogs of nucleic acids can help overcome these limitations. Herein, we show the photoprotective action of acyclothymidine dinucleosides on both plasmid and cellular DNA.

Rational design of dually active inhibitors against human immunodeficiency virus (HIV) reverse transcriptase (RT) and integrase (IN) has proved viable with 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) type of non-nucleoside RT inhibitors (NNRTIs). To establish the pharmacophore and study the structure-activity relationships (SAR) of integrase inhibition within a previously disclosed RT/IN dual inhibitor scaffold, new analogues featuring substitution at different sites of the HEPT ring were designed and synthesized. These studies have revealed an IN inhibition pharmacophore that is merged with the known RT pharmacophore through a shared C-6 benzyl group. Further SAR also demonstrated that optimal IN inhibition within our dual inhibitor scaffold requires a regiospecific (N-1) diketoacid (DKA)-carrying pendant with a certain length.

N-3-Hydroxylation of pyrimidine-2,4-diones was recently found to yield inhibitors of both HIV-1 reverse transcriptase (RT) and integrase (IN). An extended series of analogues featuring a benzoyl group at the C-6 position of the pyrimidine ring was synthesized. Through biochemical studies it was found that these new analogues are dually active against both RT and IN in low micromolar range. Antiviral assays confirmed that these new inhibitors are active against HIV-1 in cell culture at nanomolar to low micromolar range, further validating 3-hydroxypyrimidine-2,4-diones as a viable scaffold for antiviral development.

A new molecular scaffold featuring an N-hydroxyimide functionality and capable of inhibiting both reverse transcriptase (RT) and integrase (IN) of Human Immunodeficiency Virus (HIV) was rationally designed based on 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio)-thymine (HEPT) non-nucleoside RT inhibitors (NNRTIs). The design involves a minimal 3-N hydroxylation of the pyrimidine ring of HEPT compound to yield a chelating triad which, along with the existing benzyl group, appeared to satisfy major structural requirements for IN binding. In the mean time, this chemical modification did not severely compromise the compound's ability to inhibit RT. A preliminary structure-activity-relationship (SAR) study reveals that this N-3 OH is essential for IN inhibition and that the benzyl group on N-1 side chain is more important for IN binding than the one on C-6.

[reaction: see text] Mannose 6-phosphate mimics locked into the alpha-configuration and bearing hydrolase-resistant phosphate surrogates were synthesized and evaluated for binding affinity to the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R). Affinity increases as the phosphate surrogate is varied in the order malonyl ethermalonatephosphonate. An alkene cross-metathesis approach to sought-after bivalent M6P-bearing ligands is also described. These compounds were designed to map onto biantennary sectors of high-mannose-type oligosaccharides carried by glycoprotein M6P/IGF2R ligands.