Current Medicinal Chemistry - Anti-Infective Agents - Volume 4, Issue 2, 2005

This Issue of Current Medicinal Chemistry - Anti-Infective Agents focuses principally on two of the major viral pathogens impacting human health, morbidity and mortality - Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV). The selected reviews center on recent progress made on therapeutic targets that are creating optimism within the pharmaceutical and medical communities. Currently marketed HIV therapies center on three distinct targets, inhibitors of: 1. A nucleic acid viral polymerase, reverse transcriptase; both nucleoside and non-nucleoside (allosteric) inhibitors (NRTIs and NNRTIs) are available; 2. An aspartyl protease, HIV protease; and more recently; 3. Virus fusion via binding to a key fusion glycoprotein (gp41); Not surprisingly there is interest in applying the same broad notions to discover inhibitors of Hepatitis Not surprisingly there is interest in applying the same broad notions to discover inhibitors of Hepatitis C in order to complement or supplement the current treatment modalities (variations of pegylated or nonpegylated interferon with ribavirin). Thus considerable effort continues to be expended in search of inhibitors of HCV polymerase (the NS5B RNA-dependent RNA polymerase) and HCV NS3 protease. We begin this Issue with reviews that focus on specific aspects of both of these areas. In the first review, Drs. S. Condon, M. LaPorte, and T. Herbertz examine the considerable progress made on allosteric non-nucleosidic HCV RNA polymerase inhibitors in “Allosteric Inhibitors of Hepatitis C NS5B RNA-Dependent RNA Polymerase” . In the second review, Drs. S. LaPlante and M. Llinàs-Brunet provide an inside look at the story behind the discovery and progression of BILN 2061, a very potent and clinically active HCV protease inhibitor in “Dynamics and Structure-Based Design of Drugs Targeting the Critical Serine Protease of the Hepatitis C Virus - From a Peptidic Substrate to BILN 2061”. Returning to HIV this Issue focuses on two promising new mechanisms that might in the future complement the existing HIV armament. These are (1) inhibitors of virus attachment and entry through the CCR5 and CXCR4 chemokine co-receptors and (2) inhibitors of HIV DNA integrase. Thus in the third review, Drs. W. Kazmierski, J. Peckham, M. Duan, T. Kenakin, S. Jenkinson, K. Gudmundsson, S. Piscitelli and P. Feldman summarize the current state of the art for chemokine receptor antagonists as HIV entry inhibitors in “Recent Progress in the Discovery of New CCR5 and CXCR4 Chemokine Receptor Antagonists as Inhibitors of HIV-1 Entry”. In the next review, Drs. M. Witvrouw, V. Fikkert, J. Vercammen, B. Van Maele and Z. Debyser explore HIV DNA integrase inhibition in “Identification of Authentic Inhibitors of HIV-1 Integration”. Finally, Drs. L. Garuti, M. Roberti, D. Pizzirani and G. Poggi provide an overview of an opportunity for antiviral therapeutics based on a structural arylsulfone motif. This motif has generated active prototypes vs. HIV and against other non-related virus groups (rhinovirus, cytomegalovirus, etc.) in “Arylsulphones: A Promising Class of Non-Nucleoside Antiviral Agents”.

Infection with HCV is a global concern. Estimates from the WHO suggest that over 170 million people are infected worldwide with over 2.7 million people infected in the US. Current therapies including interferon (IFN-α) and ribavirin are ineffective against many HCV genotypes and a sustained viral response is difficult to achieve in many HCV patients. Inconvenient dosing regimens and overall toxicity conspire to make these current therapies inadequate. Although the recent development of pegylated interferons have shown signs of improved genotype applicability and reduced toxicity, it is believed that alternative therapies will be needed to battle this disease on a global scale. The incidence of HIV/HCV co-infection is a growing trend and our ability to effectively treat these patients is anticipated to be a significant medical challenge. For HIV-1, the successful development of nucleotide- and non-nucleotide-based reverse transcriptase inhibitors (NNRTIs) as well as HIV protease inhibitors (PIs) has afforded patients a variety of treatment options. Although 5-times more prevalent than HIV-1 infection, the development of target-directed HCV treatments has been less successful. Like HIV, the two HCV targets receiving the most attention are the protease (NS3-4A) and the polymerase (NS5B). Recently, the discovery of several classes of allosteric HCV NS5B inhibitors have been reported in the patent and scientific literature and many have made their way into clinical trials. This review will describe the nature of these novel inhibitors while drawing comparisons and contrasts to the structural biology, development, and clinical utility of HIV NNRTIs.

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide. Although a treatment of limited efficacy exists, there is an urgent need for potent antivirals that can specifically target the viral proteins that are essential for replication. We recently reported the discovery of BILN 2061, a selective and potent inhibitor of the HCV NS3 protease. When administered to HCV infected patients for two days, BILN 2061 produced an unprecedented and rapid decrease in viral load, thus demonstrating the first proof-of-concept for a new class of HCV antiviral. The BILN 2061 family of compounds was rationally designed from a peptidic substrate using dynamicsand structure-based strategies. In this review, we present an overview of the novel strategies that led to the BILN 2061 family of compounds. It includes the discovery of the original peptide as a lead, the identification of important substituents that directly contact the protease pocket, the determination of the free and protease-bound structure and dynamics features of the compounds, and the rational use of such data for medicinal chemistry purposes. Central to this was an ongoing effort to qualitatively elucidate the binding modes/roles of each substituent using a combination of data from NMR spectroscopy, structure-activity relationships, and X-ray crystallography. In addition to achieving the desired goal of initiating clinical trials with a potent inhibitor with good pharmacokinetic properties, the methodologies developed for targeting this unusual and difficult protease, which has a shallow and relatively featureless binding pocket, are expected to have general utility in other medicinal chemistry efforts.

This review addresses key medicinal chemistry issues relevant in the discovery and development of CCR5 and CXCR4 antagonists as anti-HIV drugs. Recent progress in the discovery and development of such antagonists, SAR and clinical status are reviewed.

Current strategies for the treatment of human immunodeficiency virus (HIV) infection are based on cocktails of drugs that target the viral entry step and the enzymes reverse transcriptase or protease. At present, the clinical benefit of this combination therapy for HIV-infected patients is considerable, although it is not clear how long this effect will last taking into account the emergence of multiple drug-resistant viral strains. Addition of new anti-HIV drugs targeting additional steps of the viral replication cycle may increase the potency of inhibition and prevent significant resistance development. During HIV replication, integration of the viral genome into the cellular chromosome is an essential step catalyzed by the viral integrase. Although HIV integrase is an attractive target for antiviral therapy and the focus of intensive research, to date only two classes of compounds that selectively inhibit HIV integration have been identified, namely the diketo acids and the pyranodipyrimidines. In this review we address the question why it has proven so difficult to find potent and selective integrase inhibitors; we point to potential pitfalls in defining an inhibitor as an authentic integrase inhibitor and we propose new strategies and new technologies for the discovery of genuine HIV integration inhibitors. For the diketo acids and the pyranodipyrimidines we will discuss in detail the antiviral activity, the molecular mechanism of anti-HIV action, the in vitro HIV resistance development and the clinical perspectives.

The design and development of antiviral agents are an urgent need. The continuing problem associated with the emergence of drug resistant strains stimulates for new compounds for the treatment of both chronic diseases and acute infections. A large number of arylsulphones have been reported to show potent antiviral activity. Although they have a common chemical feature, an aromatic heterocycle bearing a sulphonyl moiety, their antiviral actions are very different. Some Nsulphonyl benzimidazoles display strong antirhinovirus efficacy and good bioavailability; others inhibit HCMV and VZV at micromolar concentrations. A wide variety of arylsulphones, endowed with potent anti-HIV activity, were subjected to diverse chemical modifications to optimize their potential. Among the first representative compounds of this class, 2-nitrophenyl phenylsulphone was selected as prototype for additional studies. The replacement of the benzene ring with heterocycles led to several pyrrolyl and indolyl sulphones, some of them showed an anti-HIV-1 activity in the low nanomolar range. Moreover various cyclic systems where the sulphonyl moiety is part of the ring were found to be strong inhibitors of HIV-1.