ReviewAnti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV☆
Introduction
Within 2 years after acquired immune deficiency syndrome (AIDS) had been identified as a disease in 1981, human immunodeficiency virus (HIV) [originally called lymphadenopathy-associated virus (LAV) and human T-lymphotropic virus type III (HTLV-III), HTLV-I and -II being human T-leukaemic viruses type 1 and 2] [1], [2] was isolated as the putative cause of the disease. This launched an intensive search for compounds that would inhibit infectivity and replication of the virus and, hopefully, favourably alter the course of the disease. The first compound shown to inhibit HIV replication both in vitro (cell culture) and in vivo (HIV-infected individuals) was suramin [3], [4]. However, the first anti-HIV agent to be licensed for clinical use (in 1987) was zidovudine. It was first described in 1985 as an antiviral agent inhibiting the infectivity and cytopathic effect of HTLV-III/LAV in vitro [5].
In these early days of anti-HIV drug research, it could hardly be foreseen that within 25 years of the virus being discovered we would now, in 2008, have at hand 25 anti-HIV compounds licensed (thus formally approved) for the treatment of AIDS (Table 1). These compounds fall within different categories depending on the target within the HIV replicative cycle they interact with (Fig. 1). The targets that have been envisaged most intensively are: reverse transcription, catalysed by reverse transcriptase (RT) (RNA-dependent DNA polymerase), a specific viral enzyme that retrotranscribes the viral single-stranded RNA genome to double-stranded proviral DNA; and proteolytic processing by the viral protease, which cleaves the precursor viral polyprotein into smaller mature (both structural and functional) viral proteins. Other targets that have been recognised more recently as sites for therapeutic intervention are viral entry, particularly virus–cell fusion and interaction of the virus with its (co-)receptors, and integration of the proviral DNA into the host cell genome, a process carried out by a specific viral enzyme, integrase, which determines whether the HIV-infected cell and all daughter cells stemming thereof will permanently carry the provirus.
Section snippets
Nucleoside reverse transcriptase inhibitors (NRTIs)
The RT associated with HIV is actually the target for three classes of inhibitors: nucleoside RT inhibitors (NRTIs); nucleotide RT inhibitors (NtRTIs); and non-nucleoside RT inhibitors (NNRTIs). The NRTIs and NtRTIs interact with the catalytic site (that is the substrate-binding site) of the enzyme, whereas the NNRTIs interact with an allosteric site located at a short distance (ca. 15 Å) from the catalytic site (Fig. 2).
For the NRTIs and NtRTIs to interact with the substrate-binding site they
Nucleotide reverse transcriptase inhibitors (NtRTIs)
NtRTIs should be clearly distinguished from the NRTIs as they are nucleotide analogues (not nucleoside analogues), which means that they only need two (not three) phosphorylation steps to be converted to their active form. Most importantly, they contain a phosphonate group that cannot be cleaved by hydrolases (esterases), which would make it more difficult to cleave off these compounds, once incorporated at the 3’-terminal end, compared with their regular nucleotide counterparts (i.e. AZTMP,
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
The first two classes of compounds that could be categorised as NNRTIs, i.e. non-nucleoside HIV-1 RT inhibitors, were the HEPT [12] and TIBO [13] derivatives. They were the first to be recognised as specific inhibitors of HIV-1, interacting with an allosteric (that is non-catalytic) site of the HIV-1 RT [14]. Remarkable similarities were discerned in the structural features of the HEPT and TIBO derivatives that allowed a superposition of the prototypes of these two classes of compounds,
Protease inhibitors (PIs)
There are at present ten protease inhibitors (PIs) licensed for clinical use in the treatment of HIV infections. With the exception of tipranavir (which is based on a coumarin scaffold), all these PIs are based on the ‘peptidomimetic’ principle, that is they contain a hydroxyethylene scaffold which mimics the normal peptide linkage (cleaved by the HIV protease) but which itself cannot be cleaved (Fig. 11). They thus prevent the HIV protease from carrying out its normal function, that is the
Fusion inhibitors (FIs)
There is one fusion inhibitor (FI) currently available for the treatment of HIV infections, enfuvirtide (Fig. 14), a polypeptide of 36 amino acids that is homologous to, and engages in a coil–coil interaction with, the heptad repeat (HR) regions of the viral glycoprotein gp41 [20]. As a consequence of this interaction, fusion of the virus particle with the outer cell membrane is blocked (Fig. 15). The FI enfuvirtide is the only anti-HIV compound that has a polymeric (i.e. polypeptidic)
Co-receptor inhibitors (CRIs)
Co-receptor inhibitors (CRIs) interact with the co-receptors CCR5 or CXCR4 used by, respectively, M (macrophage)-tropic and T (lymphocyte)-tropic HIV strains (now generally termed R5 and X4 strains, respectively) to enter the target cells. Within the whole viral cell entry process, interaction of the viral glycoprotein gp120 with the co-receptor falls between the interaction of the viral glycoprotein gp120 with the CD4 receptor and fusion of the viral glycoprotein gp41 with the outer cell
Integrase inhibitors (INIs)
Although integrase has been pursued for many years as a potential target for the development of new anti-HIV compounds, the first integrase inhibitor (INI) licensed for clinical use, raltegravir, has only recently (in 2007) been approved. The HIV integrase has essentially two important catalytic functions (3’-processing and strand transfer) (Fig. 20). Raltegravir (Fig. 21) is targeted at the strand transfer reaction, and so is elvitegravir (Fig. 22), which is at present still in clinical (phase
Anti-HIV drug combinations: highly active antiretroviral therapy (HAART)
Since 1996, the importance of anti-HIV drug combination regimens has become widely accepted. What has been common practice for the treatment of tuberculosis (i.e. a combination of three tuberculostatics) has also been introduced for the treatment of AIDS: it was even given its own acronym, HAART, for highly active antiretroviral therapy. Combination of three (or more) anti-HIV compounds is aimed at the same goals as for the treatment of tuberculosis: (i) to obtain synergism between different
Conclusion
According to information from the US Centers for Disease Control and Prevention (CDC) in 2005, approximately 1 000 000–1 200 000 individuals are infected with HIV in the USA, 75% of whom (i.e. 750 000–900 000) have been diagnosed as HIV-infected. According to the Synovate Healthcare U.S. HIV Monitor Q2 2007, approximately 57% of these, that is 510 000, are on antiretroviral treatment and approximately 65% thereof (or 330 000) are on tenofovir (Atripla, Truvada or Viread), which means that tenofovir is
Acknowledgment
The author thanks Christiane Callebaut for proficient editorial assistance.
Funding: No funding sources.
Competing interests: The author is co-inventor of tenofovir.
Ethical approval: Not required.
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Corresponds to lectures given at the International Conference ‘Drug Design and Discovery for Developing Countries’, International Centre for Science and High Technology (ICS), United Nations Industrial Development Organization (UNIDO), 3–5 July 2008, Trieste, Italy, and at The Fourteenth International Congress of Virology, 10–15 August 2008, Istanbul, Turkey.