Tải bản đầy đủ - 0 (trang)


Tải bản đầy đủ - 0trang

Figure 7 Tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H )-one (TIBO) derivatives (A) R82913 and (B) R86183 (with a chlorine substituted in the 9- or 8position, respectively).

Figure 8 (A) 1-(2-Hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT). (B) 5Isopropyl-1-(ethoxymethyl)-6-benzyluracil (I-EBU, MKC-442).

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

described as HIV-1-specific RT inhibitors (for a review on the HIV-1specific RT inhibitors, see Refs. 28 and 64).

The HEPT and TIBO derivatives were discovered as the result of a

systematic evaluation for anti-HIV activity in cell culture. They were later

found to achieve their anti-HIV-1 activity through an interaction with the

HIV-1 RT. In contrast, nevirapine, pyridinone, and BHAP emerged from

a screening program for HIV-1 RT inhibitors. The anti-HIV-1 activity

of these compounds was subsequently confirmed in cell culture. Like the

HEPT and TIBO derivatives, the 2V,5V-bis-O-(tert-butyldimethylsilyl)-3Vspiro-5VV-(4VV-amino-1VV,2VV-oxathiole-2VV,2VV-dioxide)-pyrimidine (TSAO) derivatives (Fig. 9) [65,66] and a-anilinophenylacetamides (a-APA) (Fig. 10)

[67] were discovered through the evaluation of their anti-HIV activity in

cell culture. Subsequently, they were found to act as specific inhibitors of


Yet other compounds have been found to inhibit HIV-1 replication

through a specific interaction with HIV-1 RT (i.e., quinoxaline S-2720 [68],

5-chloro-3-(phenylsulfonyl)indole-2-carboxamide [69], dihydrothiazoloisoindolones [70] and a number of natural substances (e.g., calanolide A

and inophyllums, from the tropical rain forest trees Calophyllum lanigerum

and Calophyllum inophyllum, respectively) [71,72]. All these and yet other

compounds could be considered to be NNRTIs. The most potent among

the NNRTIs, some of the HEPT derivatives (E-EBU-dM) [63] and a-

Figure 9 2V,5V-Bis-O-(tert-butyldimethylsilyl)-3V-spiro-5W-(4W-amino-1W,2W-oxathiole-2W,2W-dioxide)pyrimidine (TSAO) derivatives TSAO-T, TSAO-m3T, and


Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Figure 10 a-Anilinophenylacetamide (a-APA) derivatives (A) R18893, (B)

R88703, and (C) R89439.

APA derivatives (R89439) [67], inhibit HIV-1 replication at a concentration of approximately 1 ng/mL, that is, 100,000-fold below the cytotoxicity


While the ddNs and ANPs must be converted intracellularly to

their 5V-triphosphates (ddNTPs) or diphosphate derivatives before they

can interact as competitive inhibitors/alternate substrates with regard to

the natural substrates (dNTPs), the NNRTIs do not need any metabolic

conversion to interact, noncompetitively with respect to the dNTPs, at

an allosteric, non –substrate binding site of the HIV-1 RT. Through the

analysis of NNRTI-resistant mutants, combined with site-directed mutagenesis studies, it has become increasingly clear which amino acid

residues are involved in the interaction of the NNRTIs with HIV-1 RT,

and, since the conformation of the HIV-1 RT has been resolved at 3.0

A˚ resolution [73], it is now possible to visualize the binding site of the

NNRTIs [74].

The antiviral activity spectrum of the NNRTIs is limited to HIV-1,

probably because only HIV-1 RT contains a pocket site at which the

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

NNRTIs may bind. The high specificity displayed by the NNRTIs in

their binding to HIV-1 RT signals that it should, a priori, be relatively

easy for the enzyme (and the virus) to escape the inhibitory effects of the

NNRTIs through mutations of the amino acid residues that either are

directly involved in the binding of the NNRTIs or contribute to the configuration of the pocket that is ideal for NNRTI binding.

From pilot studies carried out in the clinic with the NNRTIs TIBO

R82913 [75] and pyridinone L-697,661 [76], it appears that the compounds

are well tolerated and do not cause toxic side effects. Most of the HIV-1

isolates obtained from the patients treated with TIBO R82913 appeared to

be as sensitive to the compound as wild-type virus; only two HIV-1

variants were isolated, showing a sensitivity that was reduced 20-fold or

more than 100-fold, the latter being caused by a mutation (Tyr ! Leu) at

position 188 of the RT [77]. In fact, the latter mutation was lost upon

passaging the virus in vitro in cord blood lymphocytes. Following treatment of the patients with pyridinone L-697,661, drug-resistant HIV-1

variants appeared that contained mutations at the RT positions 103 (Lys

! Asn) and 181 (Tyr ! Cys) [76].

HIV-1 resistance to NNRTIs rapidly arises following passage of the

virus in cell culture in the presence of the compounds. The 181 Tyr ! Cys

mutation is most commonly seen, and it leads to resistance, or at least to

reduced sensitivity, to most of the NNRTIs (i.e., TIBO, HEPT, nevirapine, pyridinone, BHAP, TSAO, a-APA) [78 – 84]. The 188 Tyr ! His mutation is associated with resistance to TIBO [85], but not nevirapine [82].

The 103 Lys ! Asn mutation is associated mainly with resistance to TIBO

and pyridinone [78,85]. The 100 Leu ! Ile mutation is associated mainly

with resistance to TIBO [85,86]. The 106 Val ! Ala mutation mainly leads

to resistance to nevirapine and HEPT [83,84,87]. The 138 Glu ! Lys

mutation is responsible for resistance to TSAO [88,89]. The 190 Gly ! Glu

mutation accounts for resistance to quinoxaline [68], while also leading to a

dramatic reduction in RT activity [90]; and the 236 Pro ! Leu mutation is

responsible for resistance to BHAP [91].

The rapid emergence of drug-resistant HIV-1 mutants under selective

pressure of the HIV-1-specific RT inhibitors has been generally viewed as a

limitation for, if not an argument against, the clinical usefulness of these

compounds. Yet, several aspects of virus – drug resistance, particularly

with respect to the NNRTIs, remain to be addressed before the problem

of resistance can be fully assessed. For example, how pathogenic are drugresistant variants in comparison to wild-type virus? How readily are such

drug-resistant variants transmitted from one person to another? Do virus-

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

resistant variants persist when the drug is withdrawn, or do they readily

revert to the wild type?

Assuming that the development of drug resistance may indeed

compromise the clinical usefulness of the NNRTIs, how might this

problem be prevented or circumvented? If resistance develops to one of

the NNRTIs, treatment could be switched to any of the other NNRTIs to

which the virus has retained sensitivity. For example, 5-chloro-3-(phenylsulfonyl)indole-2-carboxamide [69] is active against the HIV-1 strains

that, because of the 103 Lys ! Asn mutation or 181 Tyr ! Cys mutation,

have acquired resistance to various other NNRTIs (i.e., TIBO, nevirapine,

pyridinone, BHAP). The a-APA derivative R89439 [67] is active against

the 100 Leu ! Ile mutant, which is resistant to the TIBO derivatives

R82913 and R86183. Within the TIBO class, a minor chemical modification, the shifting of the chlorine atom from the 9-position (R82913) to the

8-position (R86183), suffices to restore activity against the 181 Tyr ! Cys

mutant [92]. Similarly, pyridinone L-702,019, which differs from its

predecessor L-696,229 only by the addition of two chlorine atoms (in

the benzene ring) and substitution of sulfur for oxygen (in the pyridine

ring), remains remarkably active against HIV-1 mutants containing the

103 Lys ! Asn or 181 Tyr ! Cys mutation [93]. In some instances

resistance to one of the NNRTIs may even be accompanied by hypersensitivity to others: the 236 Pro ! Leu mutation, which causes resistance

to BHAP, confers 10-fold increased sensitivity to TIBO, nevirapine, and

pyridinone [91].

The 181 Tyr ! Cys mutation, which is responsible for resistance to

most NNRTIs, has been found to suppress the 215 mutation (Thr ! Phe/

Tyr), which is responsible for resistance to AZT [94], and, vice versa, the

181 Tyr ! Cys mutation can be suppressed by AZT, which thus means that

the mutations at positions 181 and 215 counteract each other. Yet other

mutations have proved to counteract each other: 236 Pro ! Leu vs 138 Glu

! Lys, and, as mentioned, 215 Thr ! Phe/Tyr vs 184 Met ! Val, and 215

Thr ! Phe/Tyr vs 74 Leu ! Val [47]. Based on the resistance mutations

that counteract each other, combinations of different drugs could be

envisaged—namely, combinations of AZT with either TIBO, a-APA,

HEPT, nevirapine, or pyridinone—and these two drug combinations

could be extended to three- or four-drug combinations by the addition of

another ddN analogue (such as 3TC) and/or another NNRTI (such as


What would seem to be an attractive approach to the prevention of

resistance development is the ‘‘knocking-out’’ strategy [95]. If NNRTIs,

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

such as BHAP (U-88204 or U-90152), are used from the start at a

sufficiently high concentration (i.e., 1 or 3 AM, respectively), they completely suppress virus replication [96,97], with the result that the virus is

‘‘knocked out’’ and does not have the opportunity to become resistant. If

U-90152 is combined with AZT, the concentrations of the individual drugs

can be lowered to achieve total virus clearance [97]. Five NNRTIs (TIBO,

HEPT, nevirapine, pyridinone, and BHAP) have been shown to ‘‘knock

out’’ HIV-1 in cell culture when used at concentrations (1 –10 Ag/mL) that

are nontoxic to the cells [95]. That the virus was really knocked out, and

thus the cell culture cleared (‘‘sterilized’’) from the HIV-1 infection by the

NNRTIs, was ascertained by two successive rounds of 35-cycle PCR

(polymerase chain reaction) analysis, which failed to reveal the presence

of any proviral DNA [95]. Thus, when used at ‘‘knocking-out’’ concentrations, the NNRTIs may be expected to effect a long-lasting suppression

of HIV-1 replication. This ‘‘knocking-out’’ phenomenon could be obtained at lower concentrations if the NNRTIs were combined with each

other, or with any of the ddN analogues (i.e., AZT), particularly if selected

on the basis of the ‘‘mutually counteracting mutation’’ principle.


An acute HIV infection can be blocked at any of the following stages of

the infection: virus adsorption, virus – cell fusion, viral uncoating, and reverse transcription. At the reverse transcriptase (RT) level, chemotherapeutic intervention could be envisaged at either the substrate or a non –

substrate binding site. Polyanionic substances (i.e., sulfated polysaccharides) prevent virus adsorption; plant lectins, succinylated (or aconitylated) albumins, and triterpene (i.e., betulinic acid) derivatives interfere

with virus – cell fusion; bicyclams inhibit viral uncoating; 2V,3V-dideoxynucleosides (ddNs) and acyclic nucleoside phosphonate analogues, following

intracellular conversion to their phosphorylated derivatives, interact with

the substrate binding site of the RT; and the nonnucleoside reverse transcriptase inhibitors (NNRTIs) are targeted at a non –substrate binding site

of HIV-1 RT. Some of these compounds (viz., bicyclams) and, among the

NNRTIs, some of the HEPT and a-APA derivatives, were found to inhibit

HIV-1 replication at concentrations (f1 ng/mL) that were 100,000-fold

or more below the cytotoxicity threshold. As a rule, it may be postulated

that the more specific the antiviral action, the more likely the development of virus – drug resistance; hence, NNRTIs, which engage in a highly

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

specific interaction with HIV-1 RT, rapidly lead to the emergence of drugresistant virus strains. To prevent such drug-resistant virus strains from

emerging, several strategies could be envisaged, the most attractive being

the combination of several drugs at concentrations high enough to ‘‘knock

out’’ the virus from the start. This ‘‘knocking-out’’ phenomenon has been

achieved with the NNRTIs, regardless of whether combined with any of

the ddN analogues, and it may be extended to combinations of drugs that

interact at targets other than the reverse transcriptase.


The original investigations of the author are supported by the Biomedical Research Programme of the European Community, the Belgian

Nationaal Fonds voor Wetenschappelijk Onderzoek, the Belgian Fonds

voor Geneeskundig Wetenschappelijk Onderzoek, the Belgian Geconcerteerde Onderzoeksacties, and the Janssen Research Foundation. I

thank Christiane Callebaut for her dedicated editorial assistance.


1. De Clercq E. New perspectives for the chemotherapy and chemoprophylaxis

of AIDS (acquired immune deficiency syndrome). Verh K Acad Geneeskd

Belg 1992; 54:57 – 89.

2. De Clercq E. Anti-HIV agents interfering with the initial stages of the HIV

replicative cycle. In: Morrow WJW, Haigwood NL, eds. HIV Molecular

Organization, Pathogenicity and Treatment. Amsterdam: Elsevier Science

Publishers, 1993:267 – 292.

3. De Clercq E. The emerging role of fusion inhibitors in HIV infection. Drug

Dev Res 1999; 2:321 – 331.

4. De Clercq E. Inhibition of HIV infection by bicyclams, highly potent and

specific CXCR4 antagonists. Mol Pharmacol 2000; 57:833 – 839.

5. De Clercq E, Schols D. Inhibition of HIV infection by CXCR4 and CCR5

chemokine receptor antagonists. Antiviral Chem Chemother 2001; 12 (suppl

1):19 – 31.

6. De Clercq E. New developments in anti-HIV chemotherapy. Curr Med

Chem 2001; 8:1543 – 1572.

7. De Clercq E. Anti-HIV activity of sulfated polysaccharides. In: Yalpani M,

ed. Carbohydrates and Carbohydrate Polymers, Analysis, Biotechnology,

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.












Modification, Antiviral, Biomedical and Other Applications. Mount Prospect, IL: ATL Press, 1993:87 – 100.

Schols D, Pauwels R, Desmyter J, De Clercq E. Presence of class II histocompatibility DR proteins on the envelope of human immunodeficiency

virus demonstrated by FACS analysis. Virology 1992; 189:374 – 376.

Callahan LN, Phelan M, Mallinson M, Norcross MA. Dextran sulfate

blocks antibody binding to the principal neutralizing domain of human

immunodeficiency virus type 1 without interfering with gp120-CD4 interactions. J Virol 1991; 65:1543 – 1550.

Batinic D, Robey FA. The V3 region of the envelope glycoprotein of human

immunodeficiency virus type 1 binds sulfated polysaccharides and CD4derived synthetic peptides. J Biol Chem 1992; 267:6664 – 6671.

Schols D, Baba M, Pauwels R, Desmyter J, De Clercq E. Specific interaction

of aurintricarboxylic acid with the human immunodeficiency virus/CD4 cell

receptor. Proc Natl Acad Sci USA 1989; 86:3322 – 3326.

Schols D, Pauwels R, Witvrouw M, Desmyter J, De Clercq E. Differential

activity of polyanionic compounds and castanospermine against HIV replication and HIV-induced syncytium formation depending on virus strain and

cell type. Antiviral Chem Chemother 1992; 3:23 – 29.

Lorentsen KJ, Hendrix CW, Collins JM, Kornhauser DM, Petty BG,

Klecker RW, Flexner C, Eckel RH, Lietman PS. Dextran sulfate is poorly

absorbed after oral administration. Ann Intern Med 1989; 111:561 – 566.

Moriya T, Saito K, Kurita H, Matsumoto K, Otake T, Mori H, Morimoto

M, Ueba N, Kunita N. A new candidate for an anti-HIV-1 agent: modified

cyclodextrin sulfate (mCDS71). J Med Chem 1993; 36:1674 – 1677.

Otake T, Schols D, Witvrouw M, Naesens L, Nakashima H, Moriya T,

Kurita H, Matsumoto K, Ueba N, De Clercq E. Modified cyclodextrin

sulphates (mCDS11) have potent inhibitory activity against HIV and high

oral bioavailability. Antiviral Chem Chemother 1994; 5:155 – 161.

Baˆrzu T, Level M, Petitou M, Lormeau J-C, J. Choay J, Schols D, Baba M,

Pauwels R, Witvrouw M, De Clercq E. Preparation and anti-HIV activity of

O-acylated heparin and dermatan sulfate derivatives with low anticoagulant

effect. J Med Chem 1993; 36:3546 – 3555.

Balzarini J, Schols D, Neyts J, Van Damme E, Peumans W, De Clercq E. a(1-3)- and a-(1-6)-d-mannose-specific plant lectins are markedly inhibitory

to human immunodeficiency virus and cytomegalovirus infections in vitro.

Antimicrob Agents Chemother 1991; 35:410 – 416.

Balzarini J, Neyts J, Schols D, Hosoya M, Van Damme E, Peumans W, De

Clercq E. The mannose-specific plant lectins from Cymbidium hybrid and

Epipactis helleborine and the (N-acetylglucosamine)n-specific plant lectin

from Urtica dioica are potent and selective inhibitors of human immunodeficiency virus and cytomegalovirus replication in vitro. Antiviral Res 1992;

18:191 – 207.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

19. Nakashima H, Masuda M, Murakami T, Koyanagi Y, Matsumoto A, Fujii

N, Yamamoto N. Anti – human immunodeficiency virus activity of a novel

synthetic peptide, T22 ([Tyr-5,12,Lys-7]polyphemusin II): a possible inhibitor of virus – cell fusion. Antimicrob Agents Chemother 1992; 36:1249 –


20. Jansen RW, Molema G, Pauwels R, Schols D, De Clercq E, Meijer DKF.

Potent in vitro anti – human immunodeficiency virus-1 activity of modified

human serum albumins. Mol Pharmacol 1991; 39:818 – 823.

21. Jansen RW, Schols D, Pauwels R, De Clercq E, Meijer DKF. Novel, negatively charged, human serum albumins display potent and selective in vitro

anti – human immunodeficiency virus type 1 activity. Mol Pharmacol 1993;

44:1003 – 1007.

22. Mayaux J-F, Bousseau A, Pauwels R, Huet T, He´nin Y, Dereu N, Evers M,

Soler F, Poujade C, De Clercq E, Le Pecq J-B. Triterpene derivatives that

block entry of human immunodeficiency virus type 1 into cells. Proc Natl

Acad Sci USA 1994; 91:3564 – 3568.

23. De Clercq E. Current lead natural products for the chemotherapy of human

immunodeficiency virus (HIV) infection. Med Res Rev 2000; 20:323 – 349.

24. De Clercq E, Yamamoto N, Pauwels R, Baba M, Schols D, Nakashima H,

Balzarini J, Debyser Z, Murrer BA, Schwartz D, Thornton D, Bridger G,

Fricker S, Henson G, Abrams M, Picker D. 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. Proc Natl Acad Sci

USA 1992; 89:5286 – 5290.

25. De Clercq E, Yamamoto N, Pauwels R, Balzarini J, Witvrouw M, De Vreese

K, Debyser Z, Rosenwirth B, Peichl P, Datema R, Thornton D, Skerlj R,

Gaul F, Padmanabhan S, Bridger G, Henson G, Abrams M. Highly potent

and selective inhibition of human immunodeficiency virus by the bicylam

derivative JM3100. Antimicrob Agents Chemother 1994; 38:668 – 674.

26. De Clercq E. HIV inhibitors targeted at the reverse transcriptase. AIDS Res

Human Retrovir 1992; 8:119 – 134.

27. De Clercq E. Hamao Umezawa Memorial Award Lecture: An odyssey in

the viral chemotherapy field. Int J Antimicrob Agents 2001; 18:309 – 328.

28. De Clercq E. New developments in anti-HIV chemotherapy. Farmaco 2001;

56:3 – 12.

29. Balzarini J, Van Aerschot A, Pauwels R, Baba M, Schols D, Herdewijn P,

De Clercq E. 5-Halogeno-3V-fluoro-2V,3V-dideoxyuridines as inhibitors of human immunodeficiency virus (HIV): potent and selective anti-HIV activity of

3V-fluoro-2V,3V-dideoxy-5-chlorouridine. Mol Pharmacol 1989; 35:571 – 577.

30. Van Aerschot A, Herdewijn P, Balzarini J, Pauwels R, De Clercq E. 3VFluoro-2V,3V-dideoxy-5-chlorouridine: most selective anti-HIV-1 agent

among a series of new 2V- and 3V-fluorinated 2V,3V-dideoxynucleoside analogues. J Med Chem 1989; 32:1743 – 1749.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

31. Schinazi RF, Chu CK, Peck A, McMillan A, Mathis R, Cannon D, Jeong

L-S, Beach JW, Choi W-B, Yeola S, Liotta DC. Activities of the four optical

isomers of 2V,3V-dideoxy-3V-thiacytidine (BCH-189) against human immunodeficiency virus type 1 in human lymphocytes. Antimicrob Agents Chemother 1992; 36:672 – 676.

32. Schinazi RF, McMillan A, Cannon D, Mathis R, Lloyd RM, Peck A,

Sommadossi J-P, St Clair M, Wilson J, Furman PA, Painter G, Choi

W-B, Liotta DC. Selective inhibition of human immunodeficiency viruses

by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother 1992; 36:2423 – 2431.

33. Huang P, Farquhar D, Plunkett W. Selective action of 3V-azido-3V-deoxythymidine 5V-triphosphate on viral reverse transcriptases and human DNA

polymerases. J Biol Chem 1990; 265:11914 – 11918.

34. McGuigan C, Pathirana RN, Balzarini J, De Clercq E. Intracellular delivery

of bioactive AZT nucleotides by aryl phosphate derivatives of AZT. J Med

Chem 1993; 36:1048 – 1052.

35. Puech F, Gosselin G, Lefebvre I, Pompon A, Aubertin A-M, Kirn A, Imbach J-L. Intracellular delivery of nucleoside monophosphates through a

reductase-mediated activation process. Antiviral Res 1993; 22:155 – 174.

36. Doong S-L, Tsai C-H, Schinazi RF, Liotta DC, Cheng Y-C. Inhibition of

the replication of hepatitis B virus in vitro by 2V,3V-dideoxy-3V-thiacytidine

and related analogues. Proc Natl Acad Sci USA 1991; 88:8495 – 8499.

37. Furman PA, Davis M, Liotta DC, Paff M, Frick LW, Nelson DJ, Dornsife

RE, Wurster JA, Wilson LJ, Fyfe JA, Tuttle JV, Miller WH, Condreay L,

Averett DR, Schinazi RF, Painter GR. The anti-hepatitis B virus activities,

cytotoxicities, and anabolic profiles of the ( – ) and (+) enantiomers of cis-5fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob

Agents Chemother 1992; 36:2686 – 2692.

38. Lin T-S, Luo M-Z, Liu M-C, Pai SB, Dutschman GE, Cheng Y-C. Antiviral

activity of 2V,3V-dideoxy-h-L-5-fluorocytidine (h-L-FddC) and 2V,3V-dideoxyh-L-cytidine (h-L-ddC) against hepatitis B virus and human immunodeficiency virus type 1 in vitro. Biochem Pharmacol 1994; 47:171 – 174.

39. Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989; 243:1731 – 1734.

40. Larder BA, Kemp SD. Multiple mutations in HIV-1 reverse transcriptase

confer high-level resistance to zidovudine (AZT). Science 1989; 246:1155 –


41. Kellam P, Boucher CAB, Larder BA. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of

high-level resistance to zidovudine. Proc Natl Acad Sci USA 1992; 89:1934 –


42. Mayers DL, McCutchan FE, Sanders-Buell EE, Merritt LI, Dilworth S,

Fowler AK, Marks CA, Ruiz NM, Richman DD, Roberts CR, Burke

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.











DS. Characterization of HIV isolates arising after prolonged zidovudine

therapy. J AIDS 1992; 5:749 – 759.

St Clair MH, Martin JL,Tudor-Williams G, Bach MC, Vavro CL, King

DM, Kellam P, Kemp SD, Larder BA. Resistance to ddI and sensitivity

to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 1991;

253:1557 – 1559.

Gao Q, Gu Z, Parniak MA, Cameron J, Cammack N, Boucher C, Wainberg

MA. The same mutation that encodes low-level human immunodeficiency

virus type 1 resistance to 2V,3V-dideoxyinosine and 2V,3V-dideoxycytidine confers high-level resistance to the ( – )enantiomer of 2V,3V-dideoxy-3V-thiacytidine. Antimicrob Agents Chemother 1993; 37:1390 – 1392.

Tisdale M, Kemp SD, Parry NR, Larder BA. Rapid in vitro selection of

human immunodeficiency virus type 1 resistant to 3V-thiacytidine inhibitors

due to a mutation in the YMDD region of reverse transcriptase. Proc Natl

Acad Sci USA 1993; 90:5653 – 5656.

Schinazi RF, Lloyd RM Jr, Nguyen M-H, Cannon DL, McMillan A, Ilksoy

N, Chu CK, Liotta DC, Bazmi HZ, Mellors JW. Characterization of human

immunodeficiency viruses resistant to oxathiolane – cytosine nucleosides.

Antimicrob Agents Chemother 1993; 37:875 – 881.

De Clercq E. HIV resistance to reverse transcriptase inhibitors. Biochem

Pharmacol 1994; 47:155 – 169.

Balzarini J, Hao Z, Herdewijn P, Johns DG, De Clercq E. Intracellular

metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylmethoxyethyl)adenine, a potent anti – human immunodeficiency virus compound. Proc Natl Acad Sci USA 1991; 88:1499 – 1503.

Balzarini J, Holy´ A, Jindrich J, Dvorakova H, Hao Z, Snoeck R, Herdewijn

P, Johns DG, De Clercq E. 9-[(2RS)-3-Fluoro-2-phosphonylmethoxypropyl]

derivatives of purines: a class of highly selective antiretroviral agents in vitro

and in vivo. Proc Natl Acad Sci USA 1991; 88:4961 – 4965.

Balzarini J, Holy´ A, Jindrich J, Naesens L, Snoeck R, Schols D, De Clercq

E. Differential antiherpesvirus and antiretrovirus effects of the (S) and (R)

enantiomers of acyclic nucleoside phosphonates: potent and selective in

vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine. Antimicrob Agents Chemother 1993; 37:332 –


Balzarini J, Naesens L, Herdewijn P, Rosenberg I, Holy´ A, Pauwels R, Baba

M, Johns DG, De Clercq E. Marked in vivo antiretrovirus activity of 9-(2phosphonylmethoxyethyl)adenine, a selective anti – human immunodeficiency virus agent. Proc Natl Acad Sci USA 1989; 86:332 – 336.

Balzarini J, Sobis H, Naesens L, Vandeputte M, De Clercq E. Inhibitory

effects of 9-(2-phosphonylmethoxyethyl)adenine and 3V-azido-2V,3V-dideoxythymidine on tumor development in mice inoculated intracerebrally with

Moloney murine sarcoma virus. Int J Cancer 1990; 45:486 – 489.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Tài liệu bạn tìm kiếm đã sẵn sàng tải về


Tải bản đầy đủ ngay(0 tr)