[Chemical reactions catalyzed by DNA polymerases].

Chemical reactions catalyzed by various DNA polymerases are discussed, including DNA chain extension, the 3'-->5'-exonuclease proofreading activity, and some other pathways of replicative repair. The contribution of DNA polymerases to the fidelity of the template-dependent synthesis is analyzed by the examples of some most typical DNA polymerases.

[The successes and problems in the treatment of HIV infection: a biochemist's view].

The problems of the effectiveness of the treatment of HIV-infected patients with 11 medicinal preparations and their combinations are discussed. 5 preparations (AZT, zalcitabine, videx, stavudine and lamivudine) are the nucleoside inhibitors of the synthesis of provirus DNA, catalyzed by inverse transcriptases; 2 preparations (nevirapine and rescriptor) are the inhibitors of this enzyme, having nonnucleoside nature, and 4 preparations (saquinarin, ritonavir, indinavir and nelfinavir) are the inhibitors of the processing of virus RNA, catalyzed by HIV protease. The modern concepts of the mechanism of action of the above-mentioned preparations are presented and the problem of the search of new effective medicinal preparations is discussed.

[Phosphorylation of 5'-O-phosphonylmethylthymidine and its incorporation into HeLa cells DNA].

[3H]5'-O-Phosphonylmethylthymidine with a specific activity of 71 Ci/mmol was obtained by isotope exchange. Its incubation with a HeLa cell culture resulted in the formation of [3H]-labeled 5'-O-(beta-phosphoryl-alpha-phosphonylmethyl)thymidine, 5'-O-(beta,gamma-diphosphoryl-alpha-phosphonylmethyl)thymidine, and [3H]DNA. This proved the ability of 5'-O-phosphonylmethylthymidine to undergo phosphorylation and incorporation into the DNA of human cells.

[Azidothymidine, blocking telomerase functioning, shortens telomeric repeats in transformed human cells].

The long-term action of azidothymidine, reverse transcriptase inhibitor, on cultivated U-937 (human promyelocyte leukemia) and MeWo (human melanoma) cells led to the concentration-dependent decrease in the length of telomeric chromosomal repeats. Telomere shortening was accompanied by temporary retardation of cell proliferation. Combined with the data obtained previously, these results suggest that azidothymidine inhibits telomerase functioning in cultivated cells.

[New nucleotide inhibitors of human DNA polymerase alpha].

2'-Deoxythymidine 5'-triphosphate and 2'-deoxyadenosine 5'-triphosphate analogs containing a methylene group between the alpha phosphorus and 5' oxygen were synthesized. The substrate properties of these compounds toward some mammalian DNA polymerases and retroviral reverse transcriptases were evaluated using a system containing phage M13mp10 DNA, a synthetic oligonucleotide, and the enzyme. The compounds containing a hydroxyl at the 3' position were incorporated into the DNA chain by DNA polymerase alpha and terminal deoxynucleotidyl transferase, but were not recognized by retroviral reverse transcriptases and mammalian DNA polymerases epsilon and beta.

[Reactions of 5'-H-phosphonates, 5'-F-phosphates, and 5'-phosphates of modified thymidines in human blood plasma].

Mechanisms and rates of hydrolytic dephosphorylation of 5'-hydrogen phosphonates, 5'-fluorophosphates, and 5'-phosphates of 3'-azido-3'-deoxythymidine, 3'-fluoro-3'-deoxythymidine, and thymidine in human blood serum were investigated. 5'-Hydrogen phosphonates of 3'-substituted thymidines are dephosphorylated 50-100 times slower than the corresponding 5'-phosphates. 5'-fluorophosphates of 3'-substituted thymidines are dephosphorylated 2 times slower than corresponding 5'-phosphates; first, substituted thymidine 5'-phosphates are formed, which are later dephosphorylated into substituted thymidines.

[Conformation of crystalline 3'-nitro-2',3'-dideoxythymidine and properties of its 5'-triphosphate as a terminator substrate of retroviral reverse transcriptase].

The structure of new nucleoside--3'-nitro-2',3'-dideoxythymidine (NIT) possessing moderate anti HIV activity in MT-4 cell culture was investigated by X-ray analysis. These data showed that conformation of NIT in crystal is similar to that of one of crystallographically independent forms of 3'-azido-2',3'-dideoxythymidine. 3'-Nitro-2',3'-dideoxythymidine 5'-triphosphate (NITTP) was synthesized and its ability to inhibit human and viral DNA polymerases was studied.

[Ways of finding inhibitors of HIV reproduction among nucleotides].

In spite of continuous broad search for inhibitors of HIV reproduction among new nucleosides, there seems to be a certain crisis in the problem. One of the probable solutions could be based on the investigation of nucleotide and/or nucleoside 5'-triphosphates with modified carbohydrate and phosphate residues. The review analyzes the current state of the problem, examining of such types of compounds in cell-free systems with DNA polymerases and in HIV-infected cell cultures.

[Inhibitory analysis of DNA polymerases from human viruses using modified substrates].

A systematic analysis of DNA polymerase of human herpes simplex type 1 virus, cytomegalovirus, and human type 2 adenovirus with the help of a broad set of modified substrates of these enzymes has been carried out. It revealed compounds capable of inhibiting the DNA synthesis catalyzed both by all three enzymes and DNA polymerase alpha from human placenta. Compounds have been found which effectively and specifically inhibit the DNA synthesis catalyzed by some of the abovementioned enzymes.