Reverse transcriptase processivity

Schupbach, J. and Boni, J. (1993) Verfahren zum Nachweis reverser Transcriptase (Process for detecting reverse transcriptase). 118 pp, 25 figs., PCT International Office Publication Nr. WO 93/23560. 

The streptovaricins inhibit the reverse transcriptase of some RNA oncogenic vimses that may be involved in the process of viral transformation (see Antiviral agents). The atropisostreptovaricins again have similar activities to the corresponding natural isomers. The streptovals and streptovarone exhibit gready improved activity against reverse transcriptase relative to the streptovaricins (85), but their in vitro activities were low (86). The damavaricins also inhibit reverse transcriptase (4) as well as tumor cell growth (87). 

Arion D, Kaushik N, McCormick S, Borkow G, Parniak MA (1998) Phenotypic mechanism of HIV-1 resistance to 3 -azido-3 -deoxythymidine (AZT) increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase, Biochem 37 15908-15917... 

Najera I, Richman DD, Olivares I, Rojas JM, Peinado MA, Perucho M, Najera R, Lopez GaHndez C (1994) Natural occurrence of drug resistance mutations in the reverse transcriptase of human immunodeficiency virus type 1 isolates. AIDS Res Hum Retroviruses 10 1479-1488 Nijhuis M, Boucher CAB, Schipper R Leitner T, Schuurman R, Albert J (1998) Stochastic processes strongly influence HIV-1 evolution during suboptimal protease inhibitor therapy. Proc Natl Acad Sci USA 95 14441-14446... 

Vergote D, Butler GS, Ooms M, Cox JH, Silva C, Hollenberg MD, Jhamandas JH, Overall CM, Power C (2006) Proteolytic processing of SDF-lalpha reveals a change in receptor specificity mediating HIV-associated neurodegeneration. Proc Nad Acad Sci USA 103(50) 19182-19187 von Giesen HJ, Roller H, Theisen A, Arendt G (2002) Therapeutic effects of nonnucleoside reverse transcriptase inhibitors on the central nervous system in HlV-1-infected patients. J Acquir Immune Defic Syndr 29(4) 363-367... 

Reverse transcriptase inhibitors prevent DNA from being produced in newly infected cells. They do not, however, prevent the reactivation of HIV from previously infected cells, the reason being that the enzyme is not involved in this process. Thus, agents that act at a later point in the replication cycle, possibly preventing reactivation, would be a major advance in the treatment of AIDs sufferers. The HIV protease inhibitors, which are currently receiving considerable attention, are believed to act in the manner depicted in Fig. 5.24. 

The HlV-1 protease is responsible for processing the protein precursors to the enzymes (integrase, protease and reverse transcriptase) and the structural proteins of the HIV-1 virus. Maw and Hall found that topological indices provide rehable QSAR models for the IC50 data of 32 HIV-1 protease inhibitors [29]. The best QSAR model, with r = 0.86, s=0.60 and q = 0.79, was obtained with the shape index Ka, the connechvity index the sum of HE-state indices for ah groups that act as... 

Enzymes in viruses We have stated that virus particles do not carry out metabolic processes. Outside of a host cell, a virus particle is metabolically inert. However, some viruses do contain enzymes which play roles in the infectious process. For instance, many viruses contain their own nucleic acid polymerases which transcribe the viral nucleic acid into messenger RNA once the infection process has begun. The retroviruses are RNA viruses which replicate inside the cell as DNA intermediates. These viruses possess an enzyme, an RNA-dependent DNA popo called reverse transcriptase, which transcribes the information in the incoming RNA into a DNA intermediate. It should be noted that reverse transcriptase is unique to the retroviruses and is not found in any other viruses or in cells. 

A number of novel spiro heterocycles, including the triazepinethione 146 have been derived from 3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one 145 by condensation with active methylene compounds <00SC1257>. A condensation process was also used to prepare tricyclic triazepinones related to the non-nucleoside reverse transcriptase inhibitor nevirapine <00JHC1539>. 

One of the first cross-coupling reactions performed on solid supports was the Stille reaction [250] which is a paUadium-catalyzed reaction of a trialkylaryl or trialkylalkenyl stannane with an aromatic iodide, bromide or triflate. In contrast to the process in liquid-phase, the organotin reagent is easily removed from the solid-phase because of the subsequent washing processes. Immobilized aryl halides have been frequently coupled with aryl and alkenylstannanes, whereas stan-nanes attached to the solid support have been used less frequently for the StiUe reaction. An example is the synthesis of a benzodiazepine library by EUman et al. Recently, a Stille cross-couphng reaction has been employed in the synthesis of al-kenyldiarylmethanes (ADAM) series of non-nucleoside HlV-1 Reverse Transcriptase Inhibitors (Scheme 3.14) [251]. 

Since one of the catalytic actions of reverse transcriptase is DNA synthesis, analogues of pyrimidine and purine nucleotides inhibit this process. A drug, zidovudine, azi-... 

Figure 20.18 The central dogma of molecular biology a summary of processes involved inflow of genetic information from DNA to protein. The diagram is a summary of the biochemical processes involved in the flow of genetic information from DNA to protein via RNA intermediates. This concept had to be revised following the discovery of the enzyme, reverse transcriptase, which catalyses information transfer from RNA to DNA (see Chapter 18). It may have to be modified in the future since changes in the fatty acid composition of phospholipids in membranes can modily the properties of proteins, and possibly their functions, independent of the genetic information within the amino acid sequence of the protein (See Chapters 7, 11 and 14).

Pyrrolopyridines substituted at the 2-position of dipyridodiazepinones have been prepared for study as nonnucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase <1997JME2430>. Compound 141, synthesized from pyrrolo[2,3-, ]pyridine as a starting material, has emerged as a novel inhibitor of HIV-1. Compound 141 acts by interfering with the initial viral entry process <2003JME4236>. 

Fig. 1.50. The function of the Rev protein in the processing of the transcripts of the Human Immunodeficincy Virns (HIV). The Rev protein is a regulatory protein reqnired for the processing of the primary transcripts of HIV. In the early stadium of viral replication, before Rev protein is available, spliced mRNA of ca. 2kb are transported to the cytosol. The spliced mRNAs are created by multiple splicing events of the primary transcript and encode the regnlatory proteins Tat, Rev and Net Once a critical level of Rev protein is formed, nnspliced (9kb) or only singly spliced (4kb) forms of the viral mRNA appear in the cytosol. These encode for strnctnral proteins and reverse transcriptase. The Rev protein binds to a particular sequence of the viral RNA, the Rev responsive element (RRE). The binding of Rev to the RRE enables the transport of unspliced viral transcript into cytosol.

TF—transframe, PR—protease, RT—reverse transcriptase, RH—RNAse H, IN—integrase. The location of the processing sites in -1 were determined by protein sequencing of HIV-1 virion proteins. 

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... 

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