Current Drug Targets - Infectious Disorders - Volume 2, Issue 1, 2002

The use of HIV protease inhibitors (PIs) may be associated with serious adverse side effects that include fat tissue redistribution, hyperlipidemia, and insulin resistance. The etiology of this toxic metabolic syndrome (commonly referred to as ’HIV lipodystrophy syndrome‘) remains to be elucidated. The interpretation of available clinical data on this subject is complicated in part by the pervasiveness of potential con- founding factors that cannot be easily eliminated or adequately controlled. Numerous investigators have examined the effects of PIs on cellular processes in model systems amenable to extensive experimental manipulations the present review primarily focuses on these efforts. The ultimate goal is the unambiguous identification of discrete cellular targets being surreptitiously impacted by PIs. SREBP and Glut4 are discussed as candidate target molecules in this context. The identification of cellular factors interacting with PIs represents a necessary first step in devising rational strategies for improvement in drug therapy.

Highly active inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and protease have made it possible to dramatically reduce virus load in HIV-positive individuals. However, the presence of viral reservoirs, the emergence of drug-resistant HIV variants and the side effects of these compounds call for research into new drugs that target different stages of the viral life cycle. One attractive target is the first step in HIV replication: entry of virus into cells. HIV entry is initiated by the attachment of the virus to the host cell membrane, which in some cases involves binding to attachment factors such as DC-SIGN. Subsequent interaction of the envelope protein(Env) with theCD4 receptor causes conformational changes that enable Env to interact with a coreceptor, generally the chemokine receptors CCR5 or CXCR4. Coreceptor engagement triggers the final conformational changes in Env, which mediate lipid mixing between the viral and cellular membranes. All of these steps are potential targets for therapeutic intervention: targeting proteins that mediate viral attachment may reduce HIV transmission, while receptor blockade will inhibit virus entry. Highly conserved domains in Env which bind to CD4 and coreceptor are promising targets for broadly neutralizing antibodies, and peptide inhibitors that bind to Env and that block membrane fusion are in advanced clinical trials. These new approaches may supplement current HIV therapy and may assist in the development of an HIV vaccine.

Despite the unprecedented successes in the therapy of HIV infection, AIDS remains a major world health problem being the first cause of death in Africa and the fourth leading cause of death worldwide. Rapid emergence of drug-resistant HIV variants and severe side effects limit the efficacy of existing therapies. The intrinsic high variability of HIV calls for combining different drugs with distinct mode of action to achieve synergistic antiviral activity. Efforts are being made to develop agents address- ing new steps in HIV replication and to optimize both antiviral activity and pharmacokinetic of the current drugs targeting reverse transcriptase and protease. The class of viral entry inhibitors is undergoing evaluation for both systemic and topical administration, and compounds targeting the fusion step may be the first to reach the market. Identification of compounds unambiguously affecting HIV replication by targeting integrase supports the potential of this crucial viral enzyme as a drug target. Targeting HIV gene regulation, which could also lead to cellular toxicity, may also become an important discovery strategy, provided that inhibitors with sufficient specificity are identified. In this review we will summarize the current understanding of the key steps in HIV life cycle in the context of representative inhibitors based on their modes of action. We then present a summary of compounds under clinical development, with the aim of providing a picture of the current potential for targeting HIV.

Pentacyclic triterpenes have been found in many plants and may be isolated from any part of the plant. Triterpene derivatives were shown to have biological activities including anti-HIV-1 and anti-cancer activities. The modes of action of the anti-HIV-1 triterpenes have been reported to be associated with the virus entry, reverse transcription, virus assembly and maturation. This review will focus on the mechanisms of action of anti-HIV triterpenes and the structural features that contribute to their anti-HIV-1 activity and site of action.

The Aspartyl protease of HIV-1 offers an excellent target for the development of specific drugs against the virus. Drugs against protease and reverse transcriptase form the basis for Highly Active Anti-Retroviral Therapy (HAART) that has been successful in improving survival rates and quality of life for HIV infected individuals. However, resistance development to these drugs is a continuing problem, demanding development of additional drugs and approaches to fight virus infection. A thorough understanding of the molecular basis for substrate and inhibitor specificity is critical to defining mecha- nisms of evasion by drug-resistant mutants as well as for the rational design of drugs able to inhibit a broad spectrum of HIV-1 variants. In this article, we describe characteristics of the protease structure and what is known regarding substrate diversity and mechanisms of cleavage. Approaches to defining substrate diversity are described as an approach to identifying optimal templates for broad-based inhibitor development.

Wide variations in the antibacterial potency and spectrum of quinolones are presumably attributable, in part, to their variable potency against the molecular targets, DNA gyrase and topoisomerase IV. In addition, susceptibility of quinolones to resistance development via known point mutations in the target genes gyrA and parC / grlA varies depending on the effective affinities of the compounds toward the mutated targets. Using a medicinal chemistry approach, a series of 8-methoxy, Non-Fluorinated Quinolones (NFQs), with fluorine in the R6 position of the traditional fluoroquinolones replaced with hydrogen, were designed to retain potency against DNA gyrase and / or topoisomerase IV with point mutations in the serine-aspartate / glutamate hotspots. This resulted in compounds with antibacterial activity against a broad-spectrum of bacterial species, including multidrug-resistant gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). The efficacy of the NFQs was also demonstrated in a murine septicemia model. Furthermore, the design of the NFQs resulted in lower acute intravenous (IV) toxicity and clastogenicity relative to their 6-fluorinated counterparts. Use of the non-fluorinated quinolone nucleus allowed exploration of new structure-activity space and generation of a series of NFQs with unique combinations of affinities toward the wild type and mutated forms of the molecular targets.

Macrolides are a diverse group of antimicrobials that are widely prescribed in clinical and veterinary medicine. Macrolides inhibit bacterial growth by interacting with the large (50S) subunit of the ribosome and thereby blocking protein synthesis. The liberal application of macrolides and the mechanistically similar lincosamide and streptogramin B compounds has in recent years led to increased prevalence of resistance to these drugs. To counteract this trend and improve the efficacy of treatment, numerous macrolide derivatives have been developed and the latest of these, the ketolides, are now becoming available for clinical use. However, in the on-going battle against resistance pathogens continual improvement of drugs will be necessary, and more efficient means of drug development are required. An indication of how rational drug design might be feasible is offered by the recent crystallographic structures of the bacterial ribosome. These structures give us a view of the macrolide target at previously unseen resolution, enabling us to understand the molecular details of macrolide interaction and resistance, and provide strong clues about potential new drug targets.

Over the past decade, levels of bacterial resistance to antibiotics have risen dramatically and ”superbugs“ resistant to most or all available agents have appeared in the clinic. Thus there is a growing need to discover and introduce new drugs. One potential source of novel antibiotics is the cationic antimicrobial peptides, which have been isolated from most living entities as components of their non-specific defenses against infectious organisms. Based on these natural templates, scores of structurally diverse antimicrobial cationic peptides have been designed, manufactured both chemically and biologically, and tested for activity against specific pathogens. A few of these peptide antibiotics have entered clinical trials to date, with mixed success. However, their diverse portfolio of structures, activity spectra, biological activities, and modes of action, provide substantial potential.

Chlamydiae cause a spectrum of diseases in multiple organ systems, and chlamydial infections of the eye lead to sequelae varying from mild conjunctivitis to blindness. This paper reviews current concepts in the pathogenesis and management of ocular chlamydial infections. Trachoma, the leading cause of preventable blindness in the world, is compared with other ocular chlamydial diseases to underscore key concepts in chlamydial pathogenesis. Emerging treatment strategies are discussed in the context of chlamydial pathogenesis and the World Health Organization initiative to eradicate trachoma by 2020.

Powerful methodologies for drug design and drug database screening and selection are presently available. Studies relating the structure of molecules to a property or a biological activity by means of statistical tools (QSPR and QSAR studies, respectively) are particularly relevant. An important point for this methodology is the use of good structural descriptors that are representative of the molecular features res- ponsible for the relevant activity. Topological indices (TIs) are two-dimensional descriptors which take into account the internal atomic arrangement of compounds, and which encode in numerical form information about molecular size, shape, branching, presence of heteroatoms and multiple bonds. The usefulness of TIs in QSPR and QSAR studies has been extensively demonstrated, and they have also been used as a measure of structural similarity or diversity by their application to databases virtually generated by computer. In this article we will briefly review the history of TIs, their advantages and limitations with respect to other descriptors, and their possibilities in drug design and database selection. These applications rely on new computational techniques such as virtual combinatorial synthesis, virtual computational screening or inverse QSAR.