Current Topics in Medicinal Chemistry, Volume 4, No. 10, 2004
Contents
Recent Advances
in the Treatment of HIV Infection
Guest
Editor: Jayaram R. Tagat
Chemokine Receptor-directed Agents as Novel
Anti-HIV-1 Therapies Pp.
1017-1033
Sander G. Mills and Julie A. DeMartino
Biochemical and
Mechanistic Basis for the Activity of Nucleoside Analogue Inhibitors of HIV
Reverse Transcriptase Pp.
1035-1044
George R. Painter, Merrick R. Almond, Shuli Mao and
Dennis C. Liotta
Recent Advances
in the Development of Next Generation Non-nucleoside Reverse Transcriptase
Inhibitors Pp. 1045-1057
Christine M. Tarby
HIV-1 Integrase
Inhibitors: A Decade of Research and Two Drugs in Clinical Trial Pp. 1059-1077
Allison A. Johnson, Christophe Marchand and Yves
Pommier
Peptidomimetic
Inhibitors of HIV Protease Pp.
1079-1095
John T. Randolph and David A. DeGoey
Non-Peptidic
HIV Protease Inhibitors Pp.
1097-1114
R. Alan Chrusciel and Joseph W. Strohbach
Abstracts
[Back to top] Chemokine
Receptor-directed Agents as Novel Anti-HIV-1 Therapies
Sander G. Mills and Julie A. DeMartino
Historically, therapeutic benefit in the treatment of human immunodeficiency virus infection (HIV-1) infection has been best achieved by targeting viral proteins like HIV protease involved in viral replication rather than host cell proteins, like CD4, which facilitate the process of viral infection. Two discoveries in 1996 presented a novel opportunity to redress this issue: 1) the understanding that heptahelical G-protein coupled chemokine receptors on the surface of T cells and macrophages functioned together with CD4 to mediate viral entry, and 2) the observation that CD4 positive T cells from individuals homozygous for the CCR5 delta 32 null allele were resistant to infection by macrophage-tropic strains of the virus in vitro and in vivo. Since that time, data demonstrating that selective blockade of two chemokine receptors, CCR5 and CXCR4, by small molecule chemokine receptor antagonists or receptor-directed biologics could robustly inhibit the infection of human peripheral blood mononuclear cells (PBMCs) by macrophage-tropic and T-cell line tropic strains respectively in vitro has validated this potential approach to therapy. Early clinical trial data now also confirms that these types of agents will have anti-viral activity in some HIV-1 infected individuals; however to date, dose limiting off-target activities have prohibited a full test of their potential clinical value. It also remains to be seen how these types of agents will fare in synergy with existing HIV-1 targeted antivirals, or those currently in development.
[Back to top] Biochemical and
Mechanistic Basis for the Activity of Nucleoside Analogue Inhibitors of HIV
Reverse Transcriptase
George R. Painter, Merrick R. Almond, Shuli Mao and
Dennis C. Liotta
HIV encodes an RNA directed DNA polymerase (reverse transcriptase, RT) that is an essential enzyme in the viral replication cycle. This enzyme catalyzes the synthesis of double stranded proviral DNA from single stranded genomic RNA via a bireactant-biproduct mechanism. The functional enzyme purified from virus particles is a complex consisting of two polypeptides of molecular weight 66,000 and 51,000. Two of the four classes of currently approved anti-HIV drugs, the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs), act by inhibiting this enzyme. In this review each step of DNA synthesis catalyzed by the RT is described and the mechanism of inhibition of catalysis and termination of DNA synthesis by NRTIs is detailed. The individual steps in the catalytic cycle and the effects that the NRTIs have on them have been examined using transient kinetic analysis. The impact of stereoisomerism and resistance mutations on the rate of NRTI triphosphate incorporation (kpol), binding in the catalytic complex (Kd) and the overall efficiency of incorporation (kpol/Kd) are summarized for lamivudine, coviracil and zalcitabine. The results provide insight into the molecular forces and structural features that make these molecules effective inhibitors.
[Back to top] Recent
Advances in the Development of Next Generation Non-nucleoside Reverse
Transcriptase Inhibitors
Christine M. Tarby
Since their discovery, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have become one of the cornerstones of highly active anti-retroviral therapy (HAART). Currently, three NNRTI agents, efavirenz, nevirapine and delavirdine are commercially available. Efavirenz and nevirapine, used in combination with nucleoside reverse transcriptase inhibitors (NRTIs), provide durable regimens with efficacy comparable to protease inhibitor (PI) containing therapies. When virological failure occurs following treatment with an NNRTI, the resistance mutations can confer reduced sensitivity to the entire agent class. Therefore, the strategy for the development of next generation NNRTIs has been to focus on compounds which have improved potencies against the clinically relevant viral mutants. Agents with improved virological profiles and which maintain the ease of administration and favorable safety profiles of the current agents should find use in anti-retroviral naïve patients as well as in components of salvage regimens in the anti-retroviral experienced patient. This review summarizes the recent developments with compounds in clinical trials as of January 2002 as well as to summarize information on new agents appearing in the primary and patent literature between January 2001 and December 2002.
[Back to top] HIV-1 Integrase
Inhibitors: A Decade of Research and Two Drugs in Clinical Trial
Allison A. Johnson, Christophe Marchand and Yves
Pommier
AIDS is currently treated with a combination therapy of reverse transcriptase and protease inhibitors. Recently, the FDA approved a drug targeting HIV-1 entry into cells. There are currently no FDA approved drugs targeting HIV-1 integrase, though many scientists and drug companies are actively in pursuit of clinically useful integrase inhibitors. The objective of this review is to provide an update on integrase inhibitors reported in the last two years, including two novel inhibitors in early clinical trials, recently developed hydroxylated aromatics, natural products, peptide, antibody and oligonucleotide inhibitors. Additionally, the proposed mechanism of diketo acid inhibition is reviewed.
[Back to top] Peptidomimetic
Inhibitors of HIV Protease
John T. Randolph and David A. DeGoey
There are currently (July, 2002) six protease inhibitors approved for the treatment of HIV infection, each of which can be classified as peptidomimetic in structure. These agents, when used in combination with other antiretroviral agents, produce a sustained decrease in viral load, often to levels below the limits of quantifiable detection, and a significant reconstitution of the immune system. Therapeutic regimens containing one or more HIV protease inhibitors thus provide a highly effective method for disease management. The important role of protease inhibitors in HIV therapy, combined with numerous challenges remaining in HIV treatment, have resulted in a continued effort both to optimize regimens using the existing agents and to identify new protease inhibitors that may provide unique properties. This review will provide an overview of the discovery and clinical trials of the currently approved HIV protease inhibitors, followed by an examination of important aspects of therapy, such as pharmacokinetic enhancement, resistance and side effects. A description of new peptidomimetic compounds currently being investigated in the clinic and in preclinical discovery will follow.
[Back to top] Non-Peptidic HIV
Protease Inhibitors
R. Alan Chrusciel and Joseph W. Strohbach
The past decade has seen many exciting achievements and advances in the treatment of HIV infection. One of the key components in this ever-evolving remedial strategy has been medicinally efficacious enzymatic inhibitors targeting the essential viral aspartyl protease. While the use of currently approved HIV protease inhibitors in concert with drugs that target the reverse transcriptase has dramatically ameliorated the disease state for many individuals, highly-structured dosing regimens accompanied by adverse side-effect profiles have led to a significant level of patient non-compliance. In addition, the development of and selection for resistant mutants have limited the long-term therapeutic outlook of the current protease inhibitors. The need for complementary agents in this salutary class addressing these challenges and opportunities is vividly clear. To this end, much attention and focus has been placed on cyclic, non-peptidic protease inhibitors, exemplified by dihydropyrones and ureas, and their possible future role in this medicinal campaign. The strategies to their design as well as their biological, pharmacokinetic and resistance profiles, and their clinical application will be discussed.