New Drug Targets for HIV

SUPPLEMENT ARTICLE New Drug Targets for HIV Pamela Bean Rogers Memorial Hospital, Oconomowoc, Wisconsin A significant number of human immunodeficien...
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SUPPLEMENT ARTICLE

New Drug Targets for HIV Pamela Bean Rogers Memorial Hospital, Oconomowoc, Wisconsin

A significant number of human immunodeficiency virus (HIV) infections have become resistant to antiretroviral treatment, which means that there is a paramount need for novel drug targets to defeat the virus. Until recently, all HIV drugs inhibited HIV replication by mechanisms operating inside infected cells. In contrast, new antiretroviral drugs operate outside infected cells. Their mechanism of action consists in inhibiting entry of the virus into cells, thereby halting the very first step of HIV replication. Examples of this new class of drugs include entry inhibitors, coreceptor antagonists, and fusion inhibitors. In addition to their novel mechanism of action, this new class of drugs also has potential action against drug-resistant HIV strains, causes minimal adverse effects, and may be administered in a simplified, once-daily dosing regimen. New classes of anti-HIV drugs—and new drugs in existing classes—represent the best hope for people infected with HIV, especially those who have exhausted current therapies. WHY DO WE NEED NEW ANTI-HIV DRUGS? Almost 50 million people worldwide are infected with HIV, and a significant number of these infections have become resistant to current antiretroviral therapies. The need to constantly develop new antiretroviral drugs to combat HIV resides in the basic fact that the replication of this virus is a very inefficient process. The viral enzymes used during replication make many mistakes while copying the parental viral genome into progeny virus, and these mistakes translate into numerous mutations. Some of these mutations contribute to make the virus resistant to antiretroviral drugs, and this resistance results in treatment failure [1]. Therefore, the need for novel targets for drugs to defeat HIV is paramount. CURRENT DRUG REGIMENS In recent years, there has been enormous progress in the treatment of HIV-related illness because of the increased use of HAART, which consists in the combined used of ⭓3 antiretroviral drugs. HAART has yielded significant improvements in prognosis and has dimin-

Reprints or correspondence: Dr. Pamela Bean, Rogers Memorial Hospital, Oconomowoc, WI 53066 ([email protected]). Clinical Infectious Diseases 2005; 41:S96–100  2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4101S1-0017$15.00

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ished the occurrence of opportunistic infections in patients who adhere to their drug treatment [2]. Almost all of the compounds that are used as part of HAART are either nucleoside reverse-transcriptase inhibitors (NRTIs), nonnucleoside reverse-transcriptase inhibitors (NNRTIs), or protease inhibitors (PIs) [3]. These 3 classes of drugs target intracellular steps in the viral life cycle mediated by 2 viral enzymes, reverse transcriptase (RT) and HIV protease. Recently, a fourth class of antiretroviral drugs has been added to the current mix, as described below. NRTIs. NRTIs were the first antiretroviral drugs used to treat HIV infection; their structures mimic those of natural nucleosides. After being phosphorylated by intracellular enzymes, they compete with natural nucleosides and are preferentially incorporated by HIV RT into new viral DNA. The incorporation of an NRTI inhibits the elongation of the new DNA chain and thereby halts the replication process. Seven NRTIs are currently available in the United States: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, and emtricitabine (table 1). There is also a new class of anti-HIV drugs called nucleotide reverse-transcriptase inhibitors; tenofovir belongs to this class. These drugs differ from NRTIs in that they require 2, rather than 3, separate chemical steps before they become active inside the target cell. Partly because of this unique chemical feature, tenofovir also carries a negative charge, which allows it to

Table 1. Current drug classes approved by the US Food and Drug Administration (FDA) or under development for the treatment of HIV/AIDS. Widely used abbreviation

Trade name

Manufacturer

Zidovudine Didanosine Zalcitabine

AZT ddI ddC

Retrovir Videx Hivid

GlaxoSmithKline Bristol-Myers Squibb Hoffman–La Roche

Lamivudine Stavudine Abacavir 3TC plus AZT

3TC d4T ABC

Epivir Zerit Ziagen Combivir

GlaxoSmithKline Bristol-Myers Squibb GlaxoSmithKline GlaxoSmithKline

FTC TDF

Trizivir Emtriva Viread

GlaxoSmithKline Gilead Sciences Gilead Sciences

DAPD MIV-310

Medivir

Emory University/University of Georgia Boehringer Ingelheim

Class, FDA status, drug name Nucleoside and nucleotide reverse-transcriptase inhibitors US FDA approved

ABC plus 3TC plus AZT Emtricitabine Tenofovir Pipeline Amdoxovir Alovudine D-D4FC Elvucitabine Nonnucleoside reverse-transcriptase inhibitors US FDA approved Nevirapine Delavirdine Efaviranz Pipeline Capravirine TMC 114/r Calanolide-A Protease inhibitors US FDA approved Saquinavir Indinavir Ritonavir Nelfinavir Amprenavir Lopinavir LPV plus RTV Atazanavir Pipeline Tipranavir TMC 114/r Fusion inhibitors (new class) Enfuvirtide

DPC-817 ACH-126,443

Reverset

Incyte/Pharmasset Achillion

NVP DLV EFV

Viramune Rescriptor Sustiva

Boehringer Pfizer (Agouron unit) DuPont/Merck Pfizer Tibotec/J&J Advanced Life Sciences/Sarawak MediChem

SQV IDV RTV NFV AMP LPV

Fortovase Crixivan Norvir Viracept Agenerase Aluviran Kaletra

Hoffman–La Roche Merck Abbott Laboratories Pfizer (Agouron unit) GlaxoSmithKline Abbott Laboratories Abbott Laboratories

ATV

Revetaz

Bristol-Meyers Squib Boehringer-Ingelheim Tibotec/J&J

T-20

Fuzeon

Roche and Trimeris

NOTE. Currently, there are 22 US FDA–approved anti-HIV drugs. They include nucleoside and nonnucleoside reverse-transcriptase inhibitors, protease inhibitors, and one fusion inhibitor. None of the currently approved drugs kills HIV, but each class slows down the replication of the virus in a particular way. “Pipeline” refers to drugs under development or in the testing process.

stay in the cells, where it is active for a longer period. As a result, it needs to be taken only once daily. There are data showing that all of the NRTIs penetrate the blood-brain barrier to varying degrees. Their concentration in CSF varies, but, thus far, zidovudine is the only drug with

proven efficacy against the neurological complications of HIV disease. NNRTIs. The NNRTIs are structurally distinct from the NRTIs and act by binding to the RT enzyme directly, at a place localized downstream from the active catalytic site. These comNew Drug Targets for HIV • CID 2005:41 (Suppl 1) • S97

pounds inhibit HIV replication by interfering with the transcriptional activity of the RT enzyme. NNRTIs show a potent antiretroviral effect, provided they are given in combination with other antiretroviral drugs. There is also a high degree of cross-resistance among the currently available NNRTIs, which means that the same mutations would confer clinical resistance to the whole class. Additional characteristics of NNRTIs are the absence of cross-resistance with NRTIs and PIs and the capacity of some of these compounds (e.g., nevirapine and efavirenz) to penetrate the blood-brain barrier. The potential role that NNRTIs play in suppressing viral replication in the CNS is still unknown. PIs. The HIV protease performs a critical function in the life cycle of HIV by cleaving the polyprotein precursors that will generate the core proteins and enzymes of mature virions. Unlike RT inhibitors, the inhibition of HIV protease affects the infected cell directly by halting the production of infectious virions. Thus far, 7 compounds of the PI class have been approved by the US Food and Drug Administration (FDA): saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavirritonavir, and atazanavir (table 1). PIs have demonstrated potent antiviral activity and clinical benefit in patients at all stages of HIV infection. Their effects have been most dramatic and sustained when they have been used in combination with RT inhibitors. Combinations of 2 PIs, instead of a single PI, are increasingly being used, because the combination increases the potency of the regimen and improves adherence to therapy. For instance, the addition of a low dose of ritonavir (100 or 200 mg b.i.d.) to saquinavir, indinavir, or amprenavir improves the pharmacokinetic profile of the regimen and also reduces pill burden, because it lowers dose frequency and thereby results in lower treatment costs. In addition, another drug was developed that combines lopinavir and ritonavir in one pill. This new combination, known as Kaletra (Abbott Laboratories), is based on an extremely potent interaction, even though the long-term benefit and toxicity of dual PI combinations remains to be fully characterized. NEW MECHANISMS FOR NEW ANTI-HIV DRUGS The 3 classes of drugs mentioned above all inhibit HIV replication by mechanisms operating inside the infected cell. The main feature of the new antiretroviral drugs is that they operate outside the cell. These new drugs act by inhibiting the entry of HIV into the target cell, thereby halting the very first step of HIV replication. In addition to their novel mechanism of action, these new drugs also have potential action against drugresistant HIV strains, cause minimal adverse effects, and may be administered in a simplified dosing regimen [4]. The process of HIV entry into cells requires 3 steps: attachment of the virus to the target cell membrane, binding of the S98 • CID 2005:41 (Suppl 1) • Bean

virus to coreceptors present at the cell surface, and fusion of the virus with the cell membrane to inject its RNA. There are new drug candidates that act at each of these steps [5]. The first step, attachment of the virus to the target cell, is mediated by the interaction of HIV gp120 with the target cell receptor CD4. With the radiographic discovery of the crystal structure of the gp120–CD4 antibody complex, we have a better understanding of how HIV enters the host cell at the molecular level. These findings are providing valuable insight into the development of entry inhibitors—new drugs that inhibit the binding of the host cell to HIV. The most recent therapeutic agents endowed with inhibitory properties against the binding of the HIV envelope gp120 to the CD4 receptor in the target cell include PRO 542, BMS-378806, TNX-355, PRO 2000, and the microbicide Cyanovirin-N [6] (table 2). The second step in the process of HIV entry, which results after gp120 binds to the CD4 receptor, is the interaction of gp120 with cellular coreceptors. Indeed, CD4 binding induces conformational changes to expose a region of gp120 that participates in coreceptor binding. There are 2 types of coreceptors, CXCR4 and CCR5 [7]. Both of these molecules are chemokine receptors, which are present in different types of cells, especially in macrophages, monocytes, and T cells. CXCR4 and CCR5 act as coreceptors for HIV-1 in these cells [8, 9]. Chemokines and their receptors are believed to be involved in the inflammatory response, mediating leukocyte movement and activation. Because binding of HIV to these coreceptors is a necessary step in the life cycle of the virus, another way to

Table 2.

New drugs under development as of March 2004.

Class, subclass, drug name Entry inhibitors CD4 and gp120 inhibitors PRO 542 and PRO 2000 BMS 378806 TNX 355 Cyanovirin-N CCR5 inhibitors SCH-C and -D UK-427,857 GSK-873,140 TAK 220 Fusion inhibitor T1249 Integrase inhibitors S-1360 L-870,812 Zinc finger inhibitors Azodicarbonamide (ADA) GPG-NH2 AXD-455

Manufacturer

Progenics Bristol-Myers Squibb Tanox/Biogen Biosyn Schering-Plough Pfizer GlaxoSmithKline Takeda Chemical Industries Roche and Trimeris GlaxoSmithKline and Shionogi Merck Hubriphar (Belgium) Tripep (Sweden) Axxima (Germany)

stop HIV is by using drugs called CXCR4 and CCR5 receptor inhibitors or coreceptor antagonists. Several candidates are currently under intense investigation, and the farthest along in studies is SCH-C (Schering C; Schering Plough). SCH-C works by blocking the CCXR5 receptor [10]. Testing SCH-C has been a long, slow process, largely because of a potential adverse effect that might affect a particular heart rhythm called the QT interval. Schering Plough has a second CCXR5 inhibitor in development, currently known as SCH-D. In laboratory studies, SCH-D appears to be more potent than SCH-C and, thus far, has not been shown to affect duration of the corrected QT interval. Studies among HIV-positive subjects, however, are just beginning, so it is currently impossible to predict whether SCHC or SCH-D will prove more beneficial overall. Additional CCR5 inhibitors in development are GW873140, TAK-220, and UK-427,857 [11, 12]. Interesting features of this class of compounds are that they appear to stick to the receptor for a very long time, which suggests that they all can be taken orally as a once-daily dose. The third and final step for virus entry into the target cell results from conformational changes produced after the binding of gp120 to CD4 and the coreceptors. These conformational changes expose another viral protein called gp41. Changes in the transmembrane protein gp41 triggers release of a peptide that is then inserted into the target cell membrane to form a pore, allowing entry of the virus. This last step is inhibited by compounds called fusion inhibitors. Today, fusion inhibitors are receiving the most attention because of the recent approval by the US FDA of the first compound of this class. Fuzeon, also called enfuvirtide or T-20, acts by inhibiting the formation of the fusion pore and the subsequent fusion of the viral membrane with the host cell membrane, which leads to virus entry [13, 14]. Targeting the fusion peptide represents an attractive method of inhibition of HIV infection and a novel addendum to the current range of drugs. THE NEWEST CLASS OF FDA-APPROVED DRUGS Enfuvirtide was granted accelerated approval by the US FDA in March 2003, on the basis of data from a 24-week analysis. It has also been approved by the European Union, Switzerland, and Canada. With its unique mechanism of action, enfuvirtide leads the first class of new anti-HIV drugs to be introduced in the last 7 years. Unlike other HIV drugs that work after HIV has entered the human immune cell, enfuvirtide works outside the CD4+ cell, blocking HIV from entering the cell. Because of its unique mode of action, enfuvirtide is effective for treatmentexperienced patients who have developed resistance to the traditional anti-HIV drugs. Interestingly, patients may still develop resistance to enfuvirtide. Enfuvirtide in combination with other antiretroviral agents

is indicated for the treatment of HIV-1 infection in treatmentexperienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy. There are no studies of enfuvirtide in antiretroviral-naive patients, and there are no results from controlled trials evaluating the effect of enfuvirtide on clinical progression of HIV. Injection site reactions are the most common adverse events associated with enfuvirtide [15]. Signs and symptoms may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. Nine percent of patients have local reactions that require analgesics or limit daily activities. As with all anti-HIV drugs, enfuvirtide presents the challenges of resistance. There have been a number of reports of resistance to enfuvirtide [16–18]. From these data, it seems that residues 36–45 of gp41 are prone to mutations, which leads to the development of resistance to the drug, even though the effect and kinetics of drug resistance can be fully determined only after long-term analysis. OTHER DRUGS UNDER DEVELOPMENT After HIV enters the host cell, it must splice its genetic material into the human DNA in the cell nucleus to replicate. The HIV enzyme called integrase is required for this process. Integrase is the last of 3 HIV enzymes, after RT and protease, to be successfully targeted by a drug. Several experimental integrase inhibitors are under study, but development of this class of drugs has been slow because the biochemistry of genome splicing is very complex and many details of the mechanism of integration and even of the protein’s 3-dimensional structure remain elusive. Recently, researchers from Merck treated monkeys with an integrase inhibitor drug (L-870812). The drug was given to 6 monkeys newly infected with a hybrid monkey-human version of HIV [19]. In 4 monkeys, virus load decreased to undetectable levels; in all 6 monkeys, only a slight decrease in numbers of CD4+ cells occurred. Researchers found that the treatment was most effective when used at the start of an infection before HIV had caused serious damage. If the drug proves to be effective in human trials, it could bolster the effectiveness of the current AIDS drugs, particularly in fighting drug-resistant strains of HIV. Another candidate in this group is S-1360, a low-molecular-weight HIV-1 integrase inhibitor for oral use, which was synthesized by Shionogi and is under clinical development in the United States [20]. Integrase as a therapeutic target presents several challenges. Whereas HIV RT and protease are required to act for a significant period of time during the life cycle of the virus, integrase acts for just a brief step during infection of the cell. This reduces the chances that a drug will interfere with integration. In addition, interfering with the integration step would not affect the yield of viable virus from infected cells. Because New Drug Targets for HIV • CID 2005:41 (Suppl 1) • S99

HIV seems to produce a great deal of mutations throughout its genes, inhibition of existing HIV integrase may merely cause the emergence of drug-resistant mutant versions. The hope is that a combination of therapies targeting different enzymes, including integrase, will convey lasting benefit to the infected person by reducing the replication rate of HIV and, therefore, the emergence of mutant strains [21]. Zinc fingers are chains of amino acids found in cellular protein that play important roles in the life cycle of a cell because they capture a zinc ion, thus contributing to the capacity of the protein to bind to RNA or DNA. Indeed, the Gag protein of HIV, which forms the nucleocapsid core of the virus, is held together by 2 zinc fingers, and these, in turn, are involved in binding and packaging viral RNA into new virions budding from an infected host cell. Zinc finger inhibitors are a new class of experimental anti-HIV drugs that prevent the Gag protein from capturing and packaging new HIV genetic material into newly budding virions [22]. Disruption of the nucleocapsid of HIV leads to the production of dysfunctional virus that cannot infect new cells. Scientists believe that the nucleocapsid core cannot mutate very easily; hence, a drug that works against zinc fingers could be effective for a long time. Unfortunately, zinc fingers are not used by HIV alone, which means that drugs that affect them could have serious adverse effects. Azodicarbonamide is one of the first zinc finger inhibitors tested against HIV, and it was relatively well tolerated, at least in lower doses, but only moderately effective at reducing HIV load in patients with advanced AIDS and virological failure. The primary adverse effect of azodicarbonamide was nephrotoxicity in the form of renal colic, nephrolithiasis, and increased serum creatinine levels, caused by the precipitation of biurea, an inactive metabolite of the drug. The clinical trial was discontinued because of these adverse effects [23]. FACTS AND FUTURE The drug development process is long and complex. Keeping track of agents as they make their way through the “pipeline” can be challenging as drug names change or pharmaceutical companies merge. Candidates are frequently withdrawn because of toxicity or lack of effectiveness in early trials, and, all too often, once-promising agents seem to stall in the pipeline or disappear with little or no explanation. It usually takes ⭓10 years for a promising candidate to wind its way through the drug development process. According to the US FDA, only 1 in 1000 compounds makes it from the laboratory to clinical trials in humans, and only 1 in 5 of those compounds that enter human trials is ever approved. Despite these facts, new classes of anti-HIV drugs—and new drugs in existing classes— represent the best hope for people infected with HIV, especially those who have exhausted current therapies. Even people whose S100 • CID 2005:41 (Suppl 1) • Bean

infecting HIV strain is resistant to drugs in all 3 existing classes stand to benefit from new agents now in the pipeline. Acknowledgments Potential conflicts of interest. P.B.: no conflicts.

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