Infectious Disorders - Drug Targets
(Formerly 'Current Drug Targets - Infectious Disorders')

ISSN: 1871-5265

Infectious Disorders – Drug Targets
Volume 6, Number 4, December 2006

Contents


Proteomics to Study Candida albicans Biology and Pathogenicity Pp. 335-341
Derek P. Thomas, Aida Pitarch, Lucia Monteoliva, Concha Gil and Jose L. Lopez-Ribot
[Abstract]


Antimycobacterial Activities of Oxazolidinones: A Review Pp. 343-354
R. Sood, T. Bhadauriya, M. Rao, R. Gautam, S. Malhotra, T. K. Barman, D. J. Upadhyay and A. Rattan
[Abstract]


Dissecting HIV Fusion: Identifying Novel Targets for Entry Inhibitors Pp. 355-367
C. Finnegan and R. Blumenthal
[Abstract]


Attacking HIV Provirus: Therapeutic Strategies to Disrupt Persistent Infection Pp. 369-376
David M. Margolis and Nancy M. Archin
[Abstract]


The Other Target for Ribosomal Antibiotics: Inhibition of Bacterial Ribosomal Subunit Formation Pp. 377-390
W. Scott Champney
[Abstract]


HIV-1 RT Nonnucleoside Inhibitors and Their Interaction with RT for Antiviral Drug Development Pp. 391-413
Zhigang Zhou, Xin Lin and Jeffry D. Madura
[Abstract]




Abstracts

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Proteomics to Study Candida albicans Biology and Pathogenicity
Derek P. Thomas, Aida Pitarch, Lucia Monteoliva, Concha Gil and Jose L. Lopez-Ribot

Candida albicans is an opportunistic pathogenic fungus capable of causing infections in an expanding population of immunosuppressed patients. The implementation of proteomics in the post-genomic era of this organism can provide vital information about its biological complexity and pathogenic traits. C. albicans proteomic analyses to date have focused on the understanding of the cell wall, virulence, dimorphism, antifungal drug effects and resistance, and serological response, among others. This exciting and rapid growing discipline should become an indispensable tool in C. albicans research, particularly to address problems that cannot be solved by genomic studies. Furthermore, in the near future it is expected that results from proteomic experiments will lead to novel techniques for the management of candidiasis.


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Antimycobacterial Activities of Oxazolidinones: A Review
R. Sood, T. Bhadauriya, M. Rao, R. Gautam, S. Malhotra, T. K. Barman, D. J. Upadhyay and A. Rattan

Oxazolidinones are a new class of totally synthetic antibacterial agents with wide spectrum of activity against a variety of clinically significant susceptible and resistant bacteria. These compounds have been shown to inhibit translation at the initiation phase of protein synthesis. DuP-721, the first oxazolidinone showed good activity against M. tuberculosis when given orally or parenterally to experimental animals but was not developed further due to lethal toxicity in animal models. Later two oxazolidinones, PNU-100480 and Linezolid, demonstrated promising antimycobacterial activities in the murine model. While Linezolid has been approved for clinical use, PNU-100480 was not been developed further. DA-7867 showed good in vitro and better in vivo efficacy than Linezolid but was poorly tolerated in rat toxicology studies. The antimycobacterial activity of AZD-2563 has not been explored. RBx 7644 had modest antimycobacterial activity while RBx 8700 has potent antibacterial and concentration dependent activity against all slow growing mycobacteria. It demonstrated better activity than RBx 7644 against MDR strains of M. tuberculosis along with intracellular activity.

Toxicity, especially myelosuppression, has been an important limiting factor for development of an oxazolidinones. The GM-CSF assay has helped in selecting molecules with less myleosuppressive potential. We report, a review on the promising antituberculosis activities of the class oxazolidinones.


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Dissecting HIV Fusion: Identifying Novel Targets for Entry Inhibitors
C. Finnegan and R. Blumenthal

Significant momentum has been recently generated in understanding the HIV fusion process. This has led to the development of a host of HIV entry inhibitors which are currently in preclinical and/or clinical development or have been approved for clinical use. In this review we update our understanding of HIV fusion, specifically highlighting novel mechanisms and agents that inhibit this process. Major focus will be placed on three key areas. Initially viral attachment will be reviewed as recent developments in this field emphasize the importance of understanding cell type specific interactions with HIV. This has aided in identifying promising targets for the development of attachment inhibitors. Secondly, we will review the role of cellular lipids in HIV entry. Glycosphingolipids have been shown to interact with different components of the HIV fusion machinery and agents that perturb glycosphingolipid biosynthesis have inhibitory effects on HIV fusion. Likewise, manipulating ceramide biosynthesis also inhibits HIV fusion. Here, we describe how manipulating cellular lipids inhibits HIV fusion and how lipid biosynthesis can be modulated to potentially prevent HIV infection. We end this review by discussing the notion of targeting select host cell proteins for HIV therapy. We will review the role of the cellular proteins PDI, defensins and cytoskeletal proteins in facilitating the fusion reaction. As our understanding of the HIV fusion process increases, the identification of targets for developing entry inhibitors becomes more diverse. Given the rapid resistance of HIV to any selective pressure this is an important avenue in the advancement of drug therapy.


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Attacking HIV Provirus: Therapeutic Strategies to Disrupt Persistent Infection
David M. Margolis and Nancy M. Archin

The therapeutic armamentarium for human immunodeficiency virus type 1 (HIV-1) infection continues to expand. New targets such as entry and integration have recently been successfully exploited. However, HIV-infected patients in need of treatment are currently committed to lifelong suppressive therapy.

The persistence of integrated HIV DNA genomes capable of producing virus is a fundamental obstacle to the eradication or cure of HIV infection. Rational molecular or pharmacologic strategies to eliminate persistent HIV proviral genomes are an unaddressed therapeutic need. Coupled with potent antiretroviral therapy, treatments that could efficiently deplete the persistent DNA reservoir of HIV could radically alter treatment paradigms.

Prior attempts to target persistent proviral infection deployed intensive antiretroviral therapy (ART) in combination with global inducers of T-cell activation. Initial trials of this approach were unsuccessful. Non-specific T-cell activation may induce high-level viral replication above a level that can be fully contained by ART, while increasing the susceptibility of uninfected cells.

Selective targeting of HIV provirus via agents that induce the expression of quiescent HIV, but have limited effects on the uninfected host cell is an alternate approach to attack latent HIV. Recent studies define the role of repressive chromatin structure in maintaining HIV quiescence, and suggest that mechanisms that remodel chromatin about the HIV promoter are a possible therapeutic target. Other studies have uncovered specific factors that may act to induce or maintain latency by limiting the efficiency of HIV gene expression. Attempts to deplete latent HIV using drugs that alter chromatin structure have entered clinical study.


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The Other Target for Ribosomal Antibiotics: Inhibition of Bacterial Ribosomal Subunit Formation
W. Scott Champney

The development of microbial resistance to practically all currently used antimicrobial agents has spurred efforts to develop new antibiotics and to identify novel targets in bacterial cells. This review summarizes the evidence for inhibition of bacterial ribosomal subunit formation as a target for many antibiotics distinct from their well-known inhibition of translation. Features of a model to explain this activity are explored. Results are presented to show the accumulation of both 30S and 50S ribosomal subunit precursors in antibiotic inhibited cells. These precursors have been characterized and are shown to bind radio-labeled drugs. Pulse and chase labeling studies have revealed the slower rates of subunit synthesis in drug treated cells compared with uninhibited controls. Resynthesis of subunits after antibiotic removal precedes recovery of control protein synthesis capacity, consistent with the model presented. Also certain mutant strains defective in different ribonuclease activities are more susceptible to antibiotic inhibition of assembly as predicted. Results indicating the equivalence of assembly inhibition and translational inhibition are described. Lastly, the identification of a 50S subunit precursor particle as a substrate for rRNA methyltransferase activity is shown. The weight of evidence presented clearly indicates that ribosomal antibiotics have a second target in cells. Inhibition of cell growth and subsequent cell death results from the activity of these antibiotics on the combined targets. The possibility of designing assembly specific inhibitors is discussed.


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HIV-1 RT Nonnucleoside Inhibitors and Their Interaction with RT for Antiviral Drug Development
Zhigang Zhou, Xin Lin and Jeffry D. Madura

Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) have become an inherent component of highly active antiretroviral therapy (HAART) in the treatment of human immunodeficiency virus type 1 (HIV-1) infections. One of the most serious problems associated with NNRTIs is that the virus exhibits resistance to the drug through mutation once the virus is exposed to the drug. New inhibitors effective against these mutants and resistant to new mutations are needed in the treatment of HIV-1 infection. Most mutations are such that larger side chain amino acids are replaced with a smaller side chain. Structural and computational approaches have been used to study the interaction between the NNRTI and RT and the dynamics of wild type mutated RT with and without a bound NNRTI to help understand the mechanism of inhibition and NNRTI resistance. It is still not understood how a NNRTI binding in a pocket, 10 Å away the polymerase active site, affects the activity of RT, although several hypotheses have been suggested. Therefore, the focus for the development of next generation NNRTIs has to be the design of compounds with an improved resistance profile. Elucidating the mechanism of the interaction between NNRTI and RT is critical if structure-based drug development for HIV-1 RT is to be successful. This calls for a better understanding of the resistance mechanism by crystallographic and computational studies. This review will take a critical look at the numerous computational studies on HIV-RT and compare those results against the current structural and experimental data available.