Targets for HIV drug development Traditional classes

The first cases of AIDS were recognized in 1981 [1]. With the realization that patients with AIDS experienced nearly universal mortality, the search for effective treatment began urgently. This search was facilitated greatly by the discovery of the causative agent, the human immunodeficiency virus (HIV) [2, 3]. It was recognized early on that the replication cycles of other animal and human retroviruses depended on the virus-specific enzyme reverse transcrip-tase, and this became the first HIV drug target. Several compounds with demonstrated activity against other retroviruses were reported to have activity against HIV in vitro by inhibiting the reverse transcriptase enzyme, such as suramin [4] and ribavirin [5]. However, clinical trials of these agents ultimately showed no clinical benefits in HIV-infected patients [6, 7].

The synthesis of the thymidine analogue, later named zidovudine, was reported originally by investigators at the Detroit Institute of Cancer Research as part of a drug discovery program for new cancer chemotherapeutic agents [8]. Lin and Prusoff [9], investigators at Yale, first reported the in vitro activity of thymidine analogues as antiviral agents. Mitsuya and colleagues [10] from the National Cancer Institute and Wellcome Research Laboratories reported the first data that zidovudine triphosphate inhibited HIV replication in vitro and advocated its "cautious exploration" in HIV-infected patients.

Shortly thereafter, zidovudine entered clinical trials in patients with symptomatic HIV disease or AIDS and proved to confer a significant short-term survival benefit: in the first clinical trial sponsored by Burroughs Wellcome and led by academic investigators from the University of Miami, it was found that 1 of 145 subjects who received zidovudine, compared to 19 of 137 subjects who received placebo, died over 8-24 weeks (p < 0.001) [11]. Together with other studies, this led to the approval of zidovudine as the first therapy for HIV infection in 1987. Zidovudine continues to be used today as a component of HIV treatment regimens. Additional nucleoside analogues were developed subsequently, and currently, eight nucleoside (or nucleotide) analogues are approved for the treatment of HIV infection.

Table 1. Approved antiretroviral drugs: 2007

Class

Year of FDA approval

HIV reverse transcriptase inhibitors:

Nucleosides/nucleotides (NRTI):

zidovudine

1987

didanosine

1991

zalcitabine*

1992

stavudine

1994

lamviudine

1995

abacavir

1998

tenofovir

2001

emtricitabine

2003

Non-nucleosides (NNRTI):

nevirapine

1996

delavirdine

1997

efavirenz

2000

HIV protease inhibitors (PI):

saquinavir

1995

ritonavir

1996

indinavir

1996

nelfinavir

1997

amprenavir**

1999

lopinavir/ritonavir

2000

fosamprenavir

2003

atazanavir

2003

tipranavir

2005

darunavir

2006

HIV entry inhibitors (EI):

enfuvirtide***

2003

* no longer available; ** available only as a liquid; *** requires subcutaneous injection.

* no longer available; ** available only as a liquid; *** requires subcutaneous injection.

A second class of reverse transcriptase inhibitors, the non-nucleosides (NNRTI), was first explored in the late 1980s. Scientists at Boehringer-Ingelheim reported a series of dipyridodizepinone compounds, including nevi-rapine, that demonstrated potent activity in vitro against HIV reverse transcriptase [12] but bound to the enzyme at a site distinct from the nucleoside analogues [13]. This distinct NNRTI binding site enabled nevirapine to have in vitro antiretroviral activity against viral strains with resistance to nucleoside analogues such as zidovudine, and, in addition, likely explained the in vitro antiretroviral synergy between the two drug classes [14]. Although, in NIH-sponsored AIDS Clinical Trials Group (ACTG) trials, resistance to nevirapine developed quickly when the drug was given alone [15], combination therapy with nevirapine and two nucleoside analogues ultimately demonstrated potent, durable antiretroviral activity in industry-sponsored studies [16], leading to the approval of nevirapine in 1996. Currently, three NNRTI are approved for the treatment of HIV infection and NNRTI-based combination regimens are a mainstay of HIV therapy.

The second mechanistically distinct class of HIV drugs are the protease inhibitors. Investigators at Kyushu University School of Medicine and Kitashita University reported that the N-terminal end of the polymerase gene of retroviruses coded for an aspartyl protease [17]. Subsequently, Kramer and colleagues from Roche and the National Cancer Institute reported that the HIV gag protein was processed by a protease, and suggested this enzyme as a target for HIV drug development [18]. The three-dimensional structure of the HIV protease enzyme was described by scientists at Merck, who identified its homodimer structure and active site and also suggested it as a target for drug therapy [19].

Groups at the National Institute of Allergy and Infectious Diseases and Upjohn identified candidate HIV protease inhibitors that demonstrated anti-retroviral activity by inhibiting proteolysis of the HIV-1 gag polyprotein p55 to the structural proteins p24 and p17 [20, 21]. Scientists at Roche described a series of peptide derivatives that mimicked the transition-state of the HIV polyproteins and potently inhibited the protease enzyme [22]. Subsequently, saquinavir, ritonavir, and indinavir were identified as compounds that potently inhibited the HIV protease in vitro [23-25]. Clinical trials sponsored both by the National Institutes of Health (NIH) and industry, and conducted by academic clinical researchers, showed these compounds had potent antiretroviral activity [26-28] and conferred clinical benefits, including reductions in HIV-related morbidity and mortality [29, 30], particularly when used in combination with nucleoside analogues. These results led to the approval in 1995-1996 of saquinavir, ritonavir, and indinavir. The widespread use of protease inhibitor-based combination therapy followed, leading in turn to dramatic reductions in HIV-related morbidity and mortality in developed countries around the world [31, 32]. Currently there are ten HIV protease inhibitors approved for the treatment of HIV infection.

Despite the availability of nucleoside analogues, NNRTIs, and protease inhibitors, some patients ultimately develop multidrug-resistant virus: for example, Richman and colleagues [33] reported that an estimated 63% of the over 130 000 Americans who received care in 1996 had HIV RNA levels greater than 500 copies/ml by 1998 and that 76% of those patients with detectable viremia had resistance to one or more antiretroviral drugs. With this in mind, the search for compounds with new mechanisms of action continued and intensified.

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