Retroviral reverse transcriptases

De Clercq E. HIV inhibitors targeted at the reverse transcriptase. AIDS Res Human Retrovir 1992 8 119-134. 

Thiourea compounds have been observed to inhibit human immunodeficiency virus (HIV) reverse transcriptase, a viral enzyme that is responsible for the reverse transcription of the retroviral RNA to proviral DNA. Phenethylthiazoylthiourea (PETT) compounds were discovered as potent inhibitors of HIV type 1 and display certain structure-activity relationships among various substituents in their structure.199 207 Furthermore, thiourea derivatives have been found to be potent and selective viral inhibitors, antifungal and antibacterial compounds.208 215... 

The isolation from a marine ascidian and subsequent structure determination of polycitone A (105) (Fig. 6) was first reported [52] by Kashman and coworkers in 1994. In this paper, the penta-O-methyl derivative was reported to inhibit the growth of SV40 transformed fibroblast cells at a concentration of 10 jtg/mL. Loya, Hizi and Kashman published [53] an extensive account of the biological activity of polycitone A in 1999 in which case inhibition of retroviral reverse transcriptases and cellular DNA polymerases was described. The isolation from an ascidian and structure determination of polycitone B (106) (Fig. 4) was subsequently reported [54] by Kashman and coworkers in 2000. Obviously, the presence of extensive bromination in both polycitone A and B make this family of compounds unique among the 3,4-diarylpyrrole natural products. 

Zidovudine, azidothymidine, AZT (Retrovir, Combivir) Antiretroviral agent Inhibits HIV replication by blocking reverse transcriptase... 

Reverse transcriptase is a retroviral-specific enzyme and is essential to the virus. Drugs that inhibit this enzyme are... 

The rapid spread of acquired immune deficiency syndrome (AIDS) has prompted numerous efforts to develop therapeutic agents against the human immunodeficiency virus type 1 (HIV-1) [2351. Efforts have focused on inhibition of the virally encoded reverse transcriptase (RT) enzyme, which is responsible for the conversion of retroviral RNA to proviral DNA. The nucleoside RT inhibitors 3 -azidothymidine (AZT) and dideoxyinosine (ddl) have proven to be clinically useful anti HIV-1 agents [236], but due to their lack of selectivity versus other DNA polymerases, these compounds are flawed by their inherent toxi-... 

The pandemic of HIV and the discovery of inhibitors of viral and retroviral enzymes (e.g., AZT, which is an inhibitor of the reverse transcriptase of HIV RT-HIV) have given rise to considerable research. In this connection, deoxynucleosides, which were previously studied as potential antitumor drugs, are receiving renewed attention by researchers. Among these latter compounds, fluorodeoxynucleosides have been the focus of many investigations. ... 

It is non-nucleotide reverse transcriptase inhibitor extensively metabolized by the CYP3A P450 isoform to hydroxylated metabolites and excreted in urine. It is indicated in combination with other anti-retroviral agents in a dose of 200 mg OD-BD for first 14 days. It is also been shown to be effective in the prevention of transmission of HIV from mother to new bom. 

The retroviral genomic RNA serves as the template for synthesis of a double-stranded DNA copy, the provirus (Figure 49-4). Synthesis of the provirus is mediated by a virus-encoded RNA-dependent DNA polymerase, or reverse transcriptase. The provirus is translocated to the nucleus and is integrated into host DNA. Transcription of this... 

Tonini, T., Claudio, P.P., Giordano, A., Romano, G. (2004). Retroviral and lentiviral vector titration by the analysis of the activity of viral reverse transcriptase. Methods Mol. Biol., 285, 155-158. 

Like all other retroviruses, human immunodeficiency virus type 1 (HIV-1) contains the multifunctional enzyme reverse transcriptase (RT). Retroviral RTs have a DNA polymerase activity that can use either an RNA or a DNA template and an RNase H activity. HIV-1 RT is essential for the conversion of single-stranded viral RNA into a linear double-stranded DNA that is subsequently integrated into the host cell chromosomes [1-4]. In this conversion process HIV-1 RT catalyzes the incorporation of approximately... 

Hughes SH, Arnold E, Hostomsky Z. RNase H of retroviral reverse transcriptases. Plainview, New York Cold Spring Harbor Laboratory Press, 1996 in press. 

Volkmann S, Wohrl BM, Tisdale M, Moelling K. Enzymatic analysis of two HIV-1 reverse transcriptase mutants with mutations in carboxyl-terminal amino acid residues conserved among retroviral ribonucleoside H. JBiol Chem 1993 268 2674-2683. 

Williams KJ, Loeb LA. Retroviral reverse transcriptases Error frequencies and mutagenesis. Cun-Top Microbiol Immunol 1992 176 165-180. 

Some well-characterized eukaryotic DNA transposons from sources as diverse as yeast and fruit flies have a structure very similar to that of retroviruses these are sometimes called retrotransposons (Fig. 26-33). Retro-transposons encode an enzyme homologous to the retroviral reverse transcriptase, and their coding regions are flanked by LTR sequences. They transpose from one position to another in the cellular genome by means of an RNA intermediate, using reverse transcriptase to make a DNA copy of the RNA, followed by integration of the DNA at a new site. Most transposons in eukaryotes use this mechanism for transposition, distinguishing them from bacterial transposons, which move as DNA directly from one chromosomal location to another (see Fig. 25-43). 

FIGURE 26-33 Eukaryotic transposons. The Ty element of the yeast Saccharomyces and the copia element of the fruit fly Drosophila serve as examples of eukaryotic transposons, which often have a structure similar to retroviruses but lack the env gene. The 8 sequences of the Ty element are functionally equivalent to retroviral LTRs. In the copia element, int and RT are homologous to the integrase and reverse transcriptase segments, respectively, of the pol gene. 

Although the existence of this enzyme may not be surprising, the mechanism by which it acts is remarkable and unprecedented. Telomerase, like some other enzymes described in this chapter, contains both RNA and protein components. The RNA component is about 150 nucleotides long and contains about 1.5 copies of the appropriate CyKx telomere repeat. This region of the RNA acts as a template for synthesis of the T -G strand of the telomere. Telomerase thereby acts as a cellular reverse transcriptase that provides the active site for RNA-dependent DNA synthesis. Unlike retroviral reverse transcriptases, telomerase copies only a small segment of RNA that it carries within itself. Telomere synthesis requires the 3 end of a chromosome as primer and proceeds in the usual 5 —>3 direction. Having syn-... 

Decatromicins A (1218) and B (1219) are produced by an Actinomadura sp. and are active against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (1229,1230). These compounds are closely related to pyrrolosporin A (1220) from Micromonospora sp. (1231,1232). The ascidian Polycitor africanus from Madagascar has afforded the new polycitone B (1221) (1233), which is related to the known polycitone A (1), a potent inhibitor of retroviral reverse transcriptases and cellular DNA polymerases (1234). The known polycitrin B was synthesized for the first time (1235). 

Loya S, Rudi A, Kashman Y, Hizi A (1999) Polycitone A, a Novel and Potent General Inhibitor of Retroviral Reverse Transcriptases and Cellular DNA Polymerases. Biochem J 344 85... 

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