Retroviral enzymes

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. ... 

Reverse transcriptase A retroviral enzyme that copies RNA into DNA. 

V-Aminoimidazole derivatives, (IV), prepared by De Clercq (5) were effective as retroviral enzyme inhibitors and used in treating HIV. 

All replication-competent retroviruses possess a characteristic enzyme, reverse transcriptase (RT), which is present at 20-70 mol/virus particle (1-3). The enzyme is cleaved, and thereby activated, from an inactive precursor by the action of another retroviral enzyme, the viral protease. All RTs possess three distinct enzymatic activities (1) an RNA-dependent DNA polymerase, which is the RT in the strict sense of the word, (2) an RNase H, and (3) a DNA-dependent DNA polymerase. After infection of a new host cell, these different activities serve in turn to synthesize a cDNA of the viral RNA, to degrade RNA from the cDNA-RNA heteroduplex, and to duplicate the cDNA strand (reviewed in ref. 4). 

In the early 1970s, Howard Temin and David Baltimore independently discovered the retroviral enzyme reverse transcriptase, an RNA-directed DNA polymerase. This discovery not only proved once again that all rules in biology have exceptions (it was thought up to that point that genome information could only flow from DNA to RNA), but it also provided a... 

Retroviruses are RNA-DNA viruses that require host-cell genome integration to complete their replication cycle. The retroviral enzyme reverse transcriptase is an RNA-dependent DNA polymerase that has important uses in recombinant DNA methodologies such as the synthesis of complementary DNA (cDNA). The human immunodeficiency virus (HIV) is the etiologic agent that causes acquired immunodeficiency syndrome (AIDS) in humans. HIV infects and destroys human T cells, which are required for immune system functions. 

Lapatto, R., Blundell, T., Hemmings, A., Overington, J., Wilderspin, A., et al. (1989) X-ray analysis of HIV-1 proteinase at 2.7 A resolution confirms structural homology among retroviral enzymes. Nature 342 299-302. 

Rapid DNA-sequencing techniques have been applied to the sequencing of RNA molecules. Through the employment of the retroviral enzyme, RNA-directed DNA polymerase, RNA may serve as a template for the synthesis of a complementary DNA (cDNA) copy which may then be sequenced. 

The carboxyl proteases are so called because they have two catalytically essential aspartate residues. They were formerly called acid proteases because most of them are active at low pH. The best-known member of the family is pepsin, which has the distinction of being the first enzyme to be named (in 1825, by T. Schwann). Other members are chymosin (rennin) cathepsin D Rhizopus-pepsin (from Rhizopus chinensis) penicillinopepsin (from Penicillium janthinel-lum) the enzyme from Endothia parasitica and renin, which is involved in the regulation of blood pressure. These constitute a homologous family, and all have an Mr of about 35 000. The aspartyl proteases have been thrown into prominence by the discovery of a retroviral subfamily, including one from HIV that is the target of therapy for AIDS. These are homodimers of subunits of about 100 residues.156,157 All the aspartyl proteases contain the two essential aspartyl residues. Their reaction mechanism is the most obscure of all the proteases, and there are no simple chemical models for guidance. 

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... 

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-... 

HIV PR and other retroviral proteases are not enzymes that have evolved to carry out a single reaction at a rapid rate, but rather enzymes with minimum specificity required to cleave the viral precursors in a specific and orderly manner. 

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