of the viral RNA genome and integrase inserts it into the chromosome of the host
cell; the protease is crucial to the replication process. The viral genome carries nine
genes, three of which code for structural proteins and six for regulatory proteins that
control the ability of the virus to infect cells. One of the features of the action of
reverse transcriptase is that it frequently mismatches bases and this is exploited in the
action of the nucleotide reverse transcriptase inhibitors (see below) which mimic
natural bases and are incorporated into the DNA strand thereby terminating the chain.
The enzyme makes an average of one mistake every time it copies the RNA so that
thousands of variants, some viable some not, are produced daily.
From a detailed knowledge of the molecular mechanisms involved in virus infec-
tion and replication, numerous potential targets for drug discovery are evident
(Fig. 18.5) but to date development has concentrated on the three viral-specific
enzymes – reverse transcriptase, protease and integrase. Inhibitors of each of these
enzymes have been developed and approved for therapeutic use against HIV-1 and(i)
gp120/gp41(ii)PR
(iv)(iii)RTINFig. 18.5Targets for the therapeutic intervention in the HIV cycle. Currently approved antiretroviral drugs block
HIV infection at different steps of the viral life cycle: (i) virus entry through their interaction with gp120 or gp41;
(ii) reverse transcription (i.e. reverse transcriptase inhibitors); (iii) integration (i.e. integrase (N) inhibitors);
and (iv) maturation (i.e. inhibitors (PR) that block the conversion of immature virus into mature infectious
virons). (Reproduced from Menendez-Arias, L. and Tozser, J. (2008). HIV-1 protease inhibitors: effects on HIV-2
replication and resistance.Trends in Pharmacological Sciences, 29 , 42–49, by permission of Elsevier Science.)723 18.2 Drug discovery