Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative

Baba, Masanori; Tanaka, Hiromichi; Clercq, Erik De; Pauwels, Rudi; Balzarini, Jan; Schols, Dominique; Nakashima, Hideki; Perno, Carlo Federico; Walker, Richard; Miyasaka, Tadashi

doi:10.1016/0006-291x(89)92756-3

Cited by 300 publications

(212 citation statements)

References 15 publications

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“…To this end, they need to be phosphorylated intracellularly by host enzymes to their 5'-triphosphate (ddNTP), which then interact as DNA chain terminators in the RT reaction (2). Other, nonnucleoside inhibitors ofthe HIV-1 RT have been recently identified (3)(4)(5) that directly interact with the enzyme at a specific target site, provisionally designated as the TIBO {tetrahydroimidazo [4,5,1- In addition to the RT, several other stages in the HIV replicative cycle, starting from the virion binding to the cells to the ultimate release (budding) of the virus particles from the cells, have been envisaged as targets for therapeutic intervention (7)(8)(9)(10). One such target is the HIV protease, and several HIV-1 protease inhibitors have been designed that appear to inhibit the enzyme, and consequently virus replication, with high specificity (11)(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event.

Clercq

Yamamoto

Pauwels

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

240

186

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A series of bicyclams have been shown to be potent and selective inhibitors of human immunodeficiency virus (HIV). The compounds are inhibitory to the replication of various HIV-1 and HIV-2 strains in various human T-cell systems, including peripheral blood lymphocytes, at 0.14-1.4 microM, without being toxic to the host cells at 2.2 mM. The bicyclam JM2763 is active against 3'-azido-3'-deoxythymidine (zidovudine; AZT)-resistant HIV-1 strains and acts additively with AZT. Mechanism of action studies revealed that the bicyclams (i.e., JM2763) interact with an early event of the retrovirus replicative cycle, which could be tentatively identified as a viral uncoating event.

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mentioning

confidence: 99%

Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event.

Clercq

Yamamoto

Pauwels

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

240

186

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“…droimidazo [4,5,1-jkl [1,4]benzodiazepin-2(lH)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine, nevirapine, and pyridinone L697,661, as well as to the nucleoside analogues 3'-azido-3'-deoxythymidine, ddI, ddC, and 9-(2-phosphonylmethoxyethyl)adenine. Pol gene nucleotide sequence analysis of the TSAO-resistant and -sensitive HIV-1 strains revealed a single amino acid substitution at position 138 (Glu --+ Lys) in the RT of all TSAO-resistant HIV-1 strains.…”

mentioning

confidence: 99%

Human immunodeficiency virus type 1 (HIV-1) strains selected for resistance against the HIV-1-specific [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro- 5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)]-beta-D-pentofurano syl (TSAO) nucleoside analogues retain sensitivity to HIV-1-specific nonnucleoside inhibitors.

Balzarini

Karlsson

Vandamme

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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We recently reported that a newly discovered class of nucleoside analogues--[2',5'-bis-O-(tert-butyldimethylsilyl)- 3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)]-beta-D - pentofuranosyl derivatives of pyrimidines and purines (designated TSAO)--are highly specific inhibitors of human immunodeficiency virus type 1 (HIV-1) and targeted at the nonsubstrate binding site of HIV-1 reverse transcriptase (RT). We now find that HIV-1 strains selected for resistance against three different TSAO nucleoside derivatives retain sensitivity to the other HIV-1-specific nonnucleoside derivatives (tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine, nevirapine, and pyridinone L697,661, as well as to the nucleoside analogues 3'-azido-3'-deoxythymidine, ddI, ddC, and 9-(2-phosphonylmethoxyethyl)adenine. Pol gene nucleotide sequence analysis of the TSAO-resistant and -sensitive HIV-1 strains revealed a single amino acid substitution at position 138 (Glu-->Lys) in the RT of all TSAO-resistant HIV-1 strains. HIV-1 RT in which the Glu-138-->Lys substitution was introduced by site-directed mutagenesis and expressed in Escherichia coli could not be purified because of rapid degradation. However, HIV-1 RT containing the Glu-138-->Arg substitution was stable. It lost its sensitivity to the TSAO nucleosides but not to the other HIV-1-specific RT inhibitors (i.e., TIBO and pyridinone). Our findings point to a specific interaction of the 4''-amino group on the 3'-spiro-substituted ribose moiety of the TSAO nucleosides with the carboxylic acid group of glutamic acid at position 138 of HIV-1 RT.

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“…1 H-NMR spectra were recorded on either Varian UNITY 200 (200 MHz) or Varian UNITY 600 (600 MHz) in CDCl 3 (or dimethyl sulfoxide (DMSO)-d 6 ) with tetramethylsilane as an internal standard. Merck Art 5554 plates precoated with silica gel 60 containing fluorescent indicator F 254 were used for thin-layer chromatography and silica gel 60 (Merck 7734, 60-200 mesh) was employed for column chromatography.…”

Section: Methodsmentioning

confidence: 99%

“…[1][2][3][4][5] It is interesting that some NNTRIs have an aromatic group at the 6 position of uracil. One compound of this type is 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) 6) and emivirine has entered clinical phase III trials. 7) Recently, Buckheit et al reported a unique and highly potent uracil derivative, 1-(3-cyclopenten-1-yl)methyl-6-(3,5-dimethylbenzoyl)-5-ethyl-2,4-pyrimidinedione (SJ-3366), which showed antiviral activity against HIV-2 as well as HIV-1.…”

mentioning

confidence: 99%

Synthesis and anti‐HIV‐1 and anti‐HCMV Activity of 1‐Substituted 3‐(3,5‐Dimethylbenzyl)uracil Derivatives.

et al. 2006

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3-(3,5-Dimethylbenzyl)uracil (3) was treated with alkyl halides in the presence of alkali to give 1-substituted congeners. Condensation of 3 with alcohols using the Mitsunobu reaction was also employed as an alternative method. The anti-HIV-1 activity of 1-substituted analogues of 3-(3,5-dimethylbenzyl)uracil was evaluated according to previously established procedures. It appeared that the nitrogen of the 1-cyanomethyl group is important for anti-HIV-1 activity, suggesting interaction with the amino acid residue of HIV-1 reverse transcriptase. 1-Arylmethyl derivatives also showed good anti-HIV-1 activity; and that of 2-and 4-picolyl derivatives was particularly excellent. These results were confirmed by Docking Studies using the program, Glide ligand docking jobs, which suggests hydrogen bonding between amide N-H of Lys 101 and nitrogen of the cyanomethyl and picolyl group.

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Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative

Cited by 300 publications

References 15 publications

Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event.

Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event.

Synthesis and anti‐HIV‐1 and anti‐HCMV Activity of 1‐Substituted 3‐(3,5‐Dimethylbenzyl)uracil Derivatives.

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