Solid-State and Solution Conformations of the Potent HIV Inhibitor, 4'-Azidothymidine

Maag, Hans; Nelson, Janis T.; Steiner, Jorge L. Rios; Prisbe, Ernest J.

doi:10.1021/jm00030a001

Cited by 45 publications

(11 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The conformation around the glycosidic bond in compounds 2, 3 and 4 was obtained from the vicinal carbon-proton couplings 3 J C2-H1′ and 3 J C6,H1′ (Davies et 1985a,b; Maag et al, 1994). Two possible solutions were found in both compounds for the glycosyl torsion angle (χ) (for compound 2, the values were χ syn =+30°and +90°, χ anti =-90°and -150°, for compound 3 χ syn =+45°and +75°, χ anti =-65°and -175°, and for compound 4 χ syn =+45°and +75°, χ anti =-80°and -160°).…”

Section: Resultsmentioning

confidence: 99%

Novel 3′-Spiro Nucleoside Analogues of TSAO-T. Part II. a Comparative Study Based on NMR Conformational Analysis in Solution and Theoretical Calculations

Álvarez

Jimeno

Gago

et al. 1998

Antivir Chem Chemother

View full text Add to dashboard Cite

The structures of two novel 3′-spiro nucleosides analogues of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-m 3 T, in solution, as derived from NMR spectroscopy are described. In these TSAO analogues the spiro amino oxathioledioxide moiety has been replaced by spiro amino oxazolone or spiro amino oxathiazoledioxide moieties. A comparative study based on theoretical calculations of the hydrophobicity, the solvation free energies and molecular electrostatic potentials (MEP) of the three compounds is also described. No significant conformational differences were detected in solution between TSAO-m 3 T and its analogues that might account for the differences observed in their inhibitory activity against HIV-1 RT. The calculated hydrophobicity (log P) values, dipole moments and the electrostatic contributions to the solvation free energies of the three spiro ring systems were also similar. However, the differences found in the calculated MEPs of the spiro systems between TSAO-m 3 T and its analogues suggest that the different electrostatic surroundings of the 4′′-amino group of the spiro moiety in the analogues may be responsible for a detrimental electrostatic interaction of the spiro rings with the Glu-B138 of RT.

show abstract

Section: Resultsmentioning

confidence: 99%

Novel 3′-Spiro Nucleoside Analogues of TSAO-T. Part II. a Comparative Study Based on NMR Conformational Analysis in Solution and Theoretical Calculations

Álvarez

Jimeno

Gago

et al. 1998

Antivir Chem Chemother

View full text Add to dashboard Cite

show abstract

“…Additionally, nucleoside analogs substituted at the 4Ј-position have also been described previously (43)(44)(45)(46). For example, 4Ј-azidothymidine and 4Ј-azidoadenosine both inhibit HIV-1 replication (46) although with potencies 200 -2000-fold less than that of EFdA.…”

Section: Discussionmentioning

confidence: 97%

Mechanism of Inhibition of HIV-1 Reverse Transcriptase by 4′-Ethynyl-2-fluoro-2′-deoxyadenosine Triphosphate, a Translocation-defective Reverse Transcriptase Inhibitor

Michailidis

Marchand

Kodama

et al. 2009

Journal of Biological Chemistry

120

173

View full text Add to dashboard Cite

Nucleoside reverse transcriptase inhibitors (NRTIs) are employed in first line therapies for the treatment of human immunodeficiency virus (HIV) infection. They generally lack a 3-hydroxyl group, and thus when incorporated into the nascent DNA they prevent further elongation. In this report we show that 4-ethynyl-2-fluoro-2-deoxyadenosine (EFdA), a nucleoside analog that retains a 3-hydroxyl moiety, inhibited HIV-1 replication in activated peripheral blood mononuclear cells with an EC 50 of 0.05 nM, a potency several orders of magnitude better than any of the current clinically used NRTIs. This exceptional antiviral activity stems in part from a mechanism of action that is different from approved NRTIs. Reverse transcriptase (RT) can use EFdA-5-triphosphate (EFdA-TP) as a substrate more efficiently than the natural substrate, dATP. Importantly, despite the presence of a 3-hydroxyl, the incorporated EFdA monophosphate (EFdA-MP) acted mainly as a de facto terminator of further RT-catalyzed DNA synthesis because of the difficulty of RT translocation on the nucleic acid primer possessing 3-terminal EFdA-MP. EFdA-TP is thus a translocation-defective RT inhibitor (TDRTI). This diminished translocation kept the primer 3-terminal EFdA-MP ideally located to undergo phosphorolytic excision. However, net phosphorolysis was not substantially increased, because of the apparently facile reincorporation of the newly excised EFdA-TP. Our molecular modeling studies suggest that the 4-ethynyl fits into a hydrophobic pocket defined by RT residues Ala-114, Tyr-115, Phe-160, and Met-184 and the aliphatic chain of Asp-185. These interactions, which contribute to both enhanced RT utilization of EFdA-TP and difficulty in the translocation of 3-terminal EFdA-MP primers, underlie the mechanism of action of this potent antiviral nucleoside.Nucleoside reverse transcriptase inhibitors (NRTIs) 4 are central components of first line regimens for treatment of HIV infections (1-6). Currently, there are eight clinically approved NRTIs: AZT, 3TC, FTC, ABC, ddI, ddC, d4T, and the nucleotide tenofovir (TFV; reviewed in Refs. 7 and 8). A structural hallmark of these NRTIs is the lack of a 3Ј-OH; it has long been considered that the absence of the 3Ј-OH is essential for antiviral activity. However, the absence of the 3Ј-OH in NRTIs also imparts detrimental properties to the inhibitor, including reduced affinity for RT compared with the analogous dNTP substrate, as well as reduced intracellular conversion to the active nucleoside triphosphate (9).Previously we described a series of 4Ј-substituted NRTIs (10) that retain the 3Ј-OH group and have excellent antiviral properties and significantly improved selectivity indices (CC 50 / EC 50 ) compared with the approved NRTIs. Furthermore, these NRTIs efficiently suppress various NRTI-resistant HIV. The most potent of these 4Ј-substituted NRTIs are the adenosine analogs that have an ethynyl group at the 4Ј position of the ribose ring. Despite their high anti-HIV activity, 4Ј-substituted compounds are susce...

show abstract

“…guanosine (4Ј-AZG), and 4Ј-azido-5-chloro-2Ј-deoxyuridine (4Ј-AZU) and found that these compounds were active against HIV-1 (18,19). With respect to their specific anti-HIV activity, Chen et al reported that following intracellular anabolic phosphorylation of 4Ј-AZT, HIV RT efficiently incorporates two consecutive 4Ј-AZT molecules preventing RT from further elongating the DNA chain (4).…”

Section: Discussionmentioning

confidence: 99%

4′-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro

Kodama

Kohgo

Kitano

et al. 2001

Antimicrob Agents Chemother

129

126

View full text Add to dashboard Cite

A series of 4′-ethynyl (4′-E) nucleoside analogs were designed, synthesized, and identified as being active against a wide spectrum of human immunodeficiency viruses (HIV), including a variety of laboratory strains of HIV-1, HIV-2, and primary clinical HIV-1 isolates. Among such analogs examined, 4′-E-2′-deoxycytidine (4′-E-dC), 4′-E-2′-deoxyadenosine (4′-E-dA), 4′-E-2′-deoxyribofuranosyl-2,6-diaminopurine, and 4′-E-2′-deoxyguanosine were the most potent and blocked HIV-1 replication with 50% effective concentrations ranging from 0.0003 to 0.01 μM in vitro with favorable cellular toxicity profiles (selectivity indices ranging 458 to 2,600). These 4′-E analogs also suppressed replication of various drug-resistant HIV-1 clones, including HIV-1M41L/T215Y, HIV-1K65R, HIV-1L74V, HIV-1M41L/T69S-S-G/T215Y, and HIV-1A62V/V75I/F77L/F116Y/Q151M. Moreover, these analogs inhibited the replication of multidrug-resistant clinical HIV-1 strains carrying a variety of drug resistance-related amino acid substitutions isolated from HIV-1-infected individuals for whom 10 or 11 different anti-HIV-1 agents had failed. The 4′-E analogs also blocked the replication of a non-nucleoside reverse transcriptase inhibitor-resistant clone, HIV-1Y181C, and showed an HIV-1 inhibition profile similar to that of zidovudine in time-of-drug-addition assays. The antiviral activity of 4′-E-thymidine and 4′-E-dC was blocked by the addition of thymidine and 2′-deoxycytidine, respectively, while that of 4′-E-dA was not affected by 2′-deoxyadenosine, similar to the antiviral activity reversion feature of 2′,3′-dideoxynucleosides, strongly suggesting that 4′-Eanalogs belong to the family of nucleoside reverse transcriptase inhibitors. Further development of 4′-E analogs as potential therapeutics for infection with multidrug-resistant HIV-1 is warranted.

show abstract

Solid-State and Solution Conformations of the Potent HIV Inhibitor, 4'-Azidothymidine

Cited by 45 publications

References 3 publications

Novel 3′-Spiro Nucleoside Analogues of TSAO-T. Part II. a Comparative Study Based on NMR Conformational Analysis in Solution and Theoretical Calculations

Novel 3′-Spiro Nucleoside Analogues of TSAO-T. Part II. a Comparative Study Based on NMR Conformational Analysis in Solution and Theoretical Calculations

Mechanism of Inhibition of HIV-1 Reverse Transcriptase by 4′-Ethynyl-2-fluoro-2′-deoxyadenosine Triphosphate, a Translocation-defective Reverse Transcriptase Inhibitor

4′-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro

Contact Info

Product

Resources

About