Nucleic acid replicators

The scientific world was amazed to hear that David Lee, from the laboratory of Reza Ghadiri (Scripps Research Institute, La Jolla, California), had found a self-replicating peptide (Lee et al., 1996) there are analogies to the experiments with oligonucleotides (see Sect. 6.4). Lee was able to show that a certain peptide, containing 32 amino acids, can both function as a matrix and also support its own synthesis autocatalytically. The information transfer is clearly more complex than that involved in nucleic acid replication. In the case of this particular peptide, both the... 

Zn Alkaline phosphatase hydrolysis of phosphate esters Peptidases hormone control DNA and RNA polymerases nucleic acid replication and polymerization... 

With the quinoline antibiotics, we have another variation on the theme already developed exploitation of a biochemical difference between an infectious organism and its host. In this case, the difference is in the nature of an enzyme involved in nucleic acid replication, as developed below. 

Orgel LE, Lohrman R. Prebiotic chemistry and nucleic acid replication. Acc Chem Res 1974 7 368-77. 

In biological systems, proteins and nucleic acids perform two major roles metabolism and conversion of materials and the storage and transmission of genetic information. Proteins are synthesized according to programs written in DNA, while nucleic acid replication and repair both require protein functionality. Proteins and nucleic acids needs each other - they are interdependent. 

Antimetabolites compete with normal endogenous substrates and cause inhibition of the processes that require those substrates. Examples include purine and pyrimidine antagonists, which prevent nucleic acid replication and cellular division in cancer chemotherapy. Another example is methotrexate, which can inhibit folic acid metabolism. 

Pentamidine is an aromatic diamidine that was initially synthesized in the 1930s in a search for hypoglycemic agents. Because of its antiprotozoal activity, pentamidine has been used extensively for treatment and chemoprophylaxis of African trypanosomiasis. The exact mechanism of action of pentamidine is not known in vitro, it has been found to interfere with folate metabolism, anaerobic glycolysis, oxidative phosphorylation, and nucleic acid replication [1], Pentamidine usually is given parenterally in a dose of 4mg/kg/day as the isethionate salt, the only preparation available in the United States [1], Administration must be parenteral because gastrointestinal absorption is poor. Adverse reactions to pentamidine appear to be dose dependent, in that a 3-g total dose, which usually is reached in the second week of parenteral therapy, frequently causes toxicity [2]. 

An alternative to the mirror image-approach is the direct selection of an aptamer from libraries of chemically modified RNAs. Many modifications in the ribose moiety of nucleic acids have been shown to dramatically increase their nuclease resistance. Modifications have to be chosen so as to be compatible with nucleic acid replicating enzymes such as reverse transcriptase, or DNA- and RNA-polymerases. The modifications most commonly used are those in which the 2 -OH group of pyrimidines is substituted by a 2 -fluoro-, or a 2 -amino group (1) [64,65],... 

The much-studied systems of nucleic acid replication and transcription, followed by translation of the nucleic acid code into protein structure has many points that can be influenced by exogenous compounds, including some alkaloids. To begin with the structural integrity of stored... 

The drug gets converted by the help of cellular enzymes into corresponding mono-, di-, and triphosphate structural analogues which strategically interfere with viral nucleic acid replication phenomenon, particularly jeopordizing the very preliminary steps involved in DNA-synthesis. It has been observed that the antiviral effect is, in certain instances, proved to be much superior to that of idoxuridine and cytarabine. 

Give the names of three important drugs that specifically interfere with viral nucleic acid replication. Discuss the synthesis of one such drug selected by you. 

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