Reverse transcriptase structure

Georgiadis MM, lessen SM, Ogata CM, Telesnitsky A, Goff SP, Hendrickson WA. Mechanistic implications from the structure of a catalytic fragment of Moloney murine leukemia virus reverse transcriptase. Structure 1995 3 879-892. 

Ren J, Milton J, Weaver KL, Short SA, Stuart DI, Stammers DK (2000) Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. Structure 8 1089-1094... 

FIGURE 7.3 Diversity of structures that interact with the (a) HIV reverse transcriptase inhibitor binding site [8] and (b) the CCR5 receptor mediating HIV-1 fusion [9],... 

Gibson W (1996) Structure and assembly of the virion. Intervirology 39 389 00 Goldman ME, Nunberg JH, O Brien JA, Quintero JC, Schleif WA, Freund KF, Gaul SL, Saari WS, Wai IS, Hoffman JM et al. (1991) Pyridinone derivatives specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc Natl Acad Sci USA... 

Hannongbua S (2006) Structural Information and Drug-Enzyme Interaction of the Non-Nucleoside Reverse Transcriptase Inhibitors Based on Computational Chemistry Approaches. 4 55-84... 

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... 

Efavirenz , a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), and a Previous Structurally Related Development Candidate... 

Jacobo-Molina A, Ding J, Nanni RG, Clark AD Jr, Lu X, Tantillo C, Williams RL, Kamer G, Ferris AL, Clark P, Hizi A, Hughes SH, Arnold E. Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. Proc Natl Acad Sci USA 1993 90 6320-6324. 

Nanni RG, Ding J, Jacobo-Molina A, Hughes SH, Arnold E. Review of HIV-1 reverse transcriptase three-dimensional structure. Implications for drug design. Perspect Drug Dis Des 1993 1 129-150. 

Figure 3.7 Structure of the HIV reverse transcriptase illustrating the location of the NNRTI binding pocket.

The human retrovirus HIV can be controlled using chemotherapy directed at the reverse transcriptase and aspartyl protease encoded by the viral genome as with other microbial pathogens, however, resistance to drug therapy becomes a major problem. Figure 7.3 shows a crystal structure (PDB 1HXW) of the HIV protease, where mutated amino acids (shown in cyan) lead to disrupted binding of the clinically effective inhibitor ritonavir [24]. 

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. 

RNA amplification by PCR has been facilitated by the use of a single heat-stable enzyme. Thus, DNA polymerase from Thermus thermophilus, which has enhanced reverse transcriptase (rT) activity in presence of manganese, can be used with one buffer system. The high temperature used for rT (70°C) to produce a complementary DNA copy from RNA, and the subsequent amplification of DNA at 60°C, increases efficiency by destabilizing secondary structures in the RNA template. This procedure has been used for the amplification of hepatitis C viral RNA (Yl). 

Already, the virion-associated reverse transcriptase has been highlighted as a target. The RT gene has been cloned, and the gene product can be produced in large quantities. Several molecules of very diverse molecular structure, such as zidovudine, suramin, and rifabutin, have been shown to cause inhibition of the... 

Quantitative Structure-Activity Relationship models are used increasingly in chemical data mining and combinatorial library design [5, 6]. For example, three-dimensional (3-D) stereoelectronic pharmacophore based on QSAR modeling was used recently to search the National Cancer Institute Repository of Small Molecules [7] to find new leads for inhibiting HIV type 1 reverse transcriptase at the nonnucleoside binding site [8]. A descriptor pharmacophore concept was introduced by us recently [9] on the basis of variable selection QSAR the descriptor pharmacophore is defined as a subset of... 

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