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VI. REVERSE TRANSCRIPTASE INHIBITORS INTERACTING WITH A NONSUBSTRATE BINDING SITE: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

VI. REVERSE TRANSCRIPTASE INHIBITORS INTERACTING WITH A NONSUBSTRATE BINDING SITE: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

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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

HIV-1 RT.

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

TSAO-e3T.



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

threshold.

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

BHAP or TSAO).

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.



VII. CONCLUSION

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.



ACKNOWLEDGMENTS

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.



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