New developments in anti-HIV chemotherapy*
Erik De Clercq
Rega Institute for Medical Research, Katholieke Universiteit
Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
Abstract: Virtually all the compounds that are currently used,
or under advanced clinical trial, for the treatment of HIV infections,
belong to one of the following classes: (i) nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs): i.e., zidovudine, didanosine, zalcitabine,
stavudine, lamivudine, abacavir, emtricitabine, tenofovir (PMPA), and
disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors
(NNRTIs): i.e., nevirapine, delavirdine, efavirenz, and emivirine; and
(iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir,
nelfinavir, and amprenavir. In addition, various other events in the
HIV replicative cycle are potential targets for chemotherapeutic intervention:
(i) viral adsorption, through binding to the viral envelope glycoprotein
gp120; (ii) viral entry, through blockade of the viral coreceptors CXCR4
and CCR5; (iii) virus-cell fusion; (iv) viral assembly and disassembly;
(v) proviral DNA integration; and (vi) viral mRNA transcription. Also,
new NRTIs, NNRTIs, and PIs have been developed that possess respectively
improved metabolic characteristics, or increased activity against NNRTI-resistant
HIV strains or, as in the case of PIs, a different, nonpeptidic scaffold.
Given the multitude of molecular targets with which anti-HIV agents
can interact, one should be cautious in extrapolating from cell-free
enzymatic assays to the mode of action of these agents in intact cells.
*Lectures presented at the XVIth International Symposium
on Medicinal Chemistry, Bologna, Italy, 18-22 September 2000. Other
presentations are published in this issue, pp.
55-75.
