ABSTRACT:The main disadvantages of 3-azido-3-deoxythymidine (zidovudine, AZT), the most common anti-HIV drug, are toxicity and a short halflife in the organism. The introduction of an H-phosphonate group into the AZT 5 position resulted in significant improvement of its therapeutic properties and allowed a new anti-HIV drug, Nikavir (AZT H-phosphonate). In this work, we described a new group of AZT derivatives, namely, AZT 5-aminocarbonylphosphonates. The synthesized compounds displayed antiviral properties in cell cultures infected with HIV-1 and the capacity to release the active nucleoside in animals (rabbits and dogs) in a dose-dependent manner. The compounds were less toxic in MT-4 and HL-60 cell cultures and experimental animals compared with AZT. Major metabolites found in MT-4 cells after their incubation with AZT 5-aminocarbonylphosphonate 1 were AZT and AZT 5-phosphate (25 and 55%, respectively). Among the tested compounds, phosphonate 1 was the most effective AZT donor, and its longest t 1/2 and T max values in the line phosphonate 1 -AZT H-phosphonate -AZT imply that compound 1 is an extended depot form of AZT. Although bioavailability of AZT after oral administration of phosphonate 1 was lower than those of AZT H-phosphonate and AZT (8 against 14 and 49%), we expect that this reduction would not cause essential decrease of antiviral activity but noticeably decrease toxicity as a result of gradual accumulation of AZT in blood and the absence of sharp difference between C max and C min . Such a combination of properties makes the compounds of this group promising for further studies as extended-release forms of AZT.The progress toward the treatment of HIV infections has steadily increased in the past 2 decades. At the end of the 1980s, the life expectancy of HIV-infected patients was only 2 to 5 years, whereas today many patients often survive between 10 and 15 years; however, once the infection progresses to full-blown AIDS, the mortality rate is 100%. Currently, more than 20 drugs have been approved for treatment of HIV; these include inhibitors of crucial viral enzymes such as reverse transcriptase, protease, and integrase. Despite significant progress in the design of anti-HIV drugs, many problems remain, such as toxicity and side effects, as well as rapid elimination from the body, resulting in more frequent dosing. More significantly, the development of drug-resistant strains has increased dramatically. As a result, there is a critical need for more effective and less toxic therapeutics.In that regard, HIV reverse transcriptase has proven to be an attractive target. HIV reverse transcriptase inhibitors are primarily modified nucleosides that are converted by way of an intracellular cascade of phosphorylations to the corresponding triphosphates. The triphosphates are then incorporated into the growing DNA chain, which results in termination of DNA synthesis. As the efficacy of the triphosphates is low, drug doses must therefore be high, which generally leads to significant toxicity. One solution ...

Poly-(ADP-ribosyl)-ation (PARylation) is a reversible post-translational modification of proteins and DNA that plays an important role in various cellular processes such as DNA damage response, replication, transcription, and cell death. Here we designed a fully genetically encoded fluorescent sensor for poly-(ADP-ribose) (PAR) based on Förster resonance energy transfer (FRET). The WWE domain, which recognizes iso-ADP-ribose internal PAR-specific structural unit, was used as a PAR-targeting module. The sensor consisted of cyan Turquoise2 and yellow Venus fluorescent proteins, each in fusion with the WWE domain of RNF146 E3 ubiquitin ligase protein. This bipartite sensor named sPARroW (sensor for PAR relying on WWE) enabled monitoring of PAR accumulation and depletion in live mammalian cells in response to different stimuli, namely hydrogen peroxide treatment, UV irradiation and hyperthermia.

Photochemically induced thrombosis of blood vessels in the prefrontal cortex in rats was shown to lead to ischemic infarcts in the lesion zone. Bilateral ischemic lesioning of the prefrontal cortex degraded measures of spatial memory when animals were tested in a Morris water maze with an invisible platform 20-24 days after surgery. Chronic intranasal administration of the peptide Met-Glu-His-Phe-Pro-Gly-Pro (Semax), a synthetic analog of ACTH(4-7), at a dose of 250 microg/kg/day during the first six days after photothrombosis, led to recovery of the animals' learning ability. The long-term antiamnestic action of the peptide observed here may result from its neuroprotective activity and its ability to stimulate the synthesis of neurotrophic factors.

Nearly 30 synthetic nucleosides were tested with human recombinant poly(ADP-ribose) polymerase 1 as potential inhibitors of this enzyme. The most active compounds were some disaccharide analogues of thymidine: 3'-O-β-D-ribofuranosyl-5-iodo-dUrd (2d; IC₅₀ = 45 μM), 3'-O-β-D-ribofuranosyl-2'-deoxythymidine (2e; IC₅₀ = 38 μM), and 3'-O-β-D-ribofuranosyl-2'-deoxythymidine oxidized (4; IC₅₀ = 25 μM). These compounds also reduced H₂O₂-induced synthesis of poly(ADP-ribose) in cultured human ovarian carcinoma (SKOV-3) cells in a dose-dependent manner. Furthermore, compounds 2d or 2e until a concentration of 1 mM did not affect growth of SKOV-3 cells, whereas dialdehyde compound 4, as well as thymidine, exhibited a significant cytotoxicity.