Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 8, Issue 2, 2009

TNF-related apoptosis inducing ligand (TRAIL) is a key mediator of the innate immune response to infection. While TRAIL-mediated apoptosis plays an essential role in the clearance of virus-infected cells, its physiologic role also includes immunosurveilance for cancer cells. Therapeutics that induce TRAIL-mediated apoptosis in cancer cells remain a focus of ongoing investigation in clinical trials, and much has been learned from these studies regarding the efficacy and toxicity of these interventions. These data, combined with data from numerous preclinical studies that detail the important and multifaceted role of TRAIL during infection with human immunodeficiency virus and other viruses, suggest that therapeutic exploitation of TRAIL signaling offers a novel and efficacious strategy for the management of infectious diseases.

In recent years, significant progress has been made in the treatment of chronic hepatitis B. Currently four nucleoside analogues (lamivudine, adefovir, entecavir, and telbivudine) are available for the treatment of chronic hepatitis B virus (HBV) infection. The oral nucleos(t)ide analogues are generally better tolerated than interferon, but when administered for lengthy periods, a major concern is the antiviral-resistant mutation of HBV. Lamivudine, the first approved nucleoside analogue for the treatment of HBV infection, has been shown to be effective in suppressing HBV replication, so to ameliorate liver disease and prolong treatment with lamivudine has been shown to reverse fibrosis and cirrhosis. Among the approved nucleos(t)ide analogues (NAs) for hepatitis B, lamivudine has the highest and entacevir the lowest resistant rate for HBV. Adefovir is effective in suppressing wild type as well as lamivudine-resistance mutants. Telbivudine is more potent than lamivudine in suppressing HBV replication. On the other hand, telbivudine is associated with high rate of resistance. Combination therapy has been recently developed in order to increase efficacy and to decrease the occurrence of viral resistance. However, so far few combinations have been evaluated. No combination therapy demonstrated greater benefit as compared with monotherapy in inducing a higher rate of sustained response. However, in lamivudine-resistant HBV-infected individuals combination therapy of lamivudine and adefovir is more effective than adefovir monotherapy. More potent drugs and new combinations together with the understanding of the mechanisms of resistance to therapy are important challenges to improve the efficacy of treatment and to reduce the global disease burden related to chronic hepatitis B.

The first function attributed to lactoferrin, an iron-binding protein belonging to the non-immune natural defences, was antimicrobial activity related to its capability of sequestering iron. Many other antimicrobial and antiviral functions have been ascribed to lactoferrin. In vitro activity towards human pathogenic fungi on the part of both human and bovine lactoferrin has been well documented as well. The antifungal activity appears to be related to lactoferrin interference with the fungal cell surface rather than iron deprivation and some host-mediated mechanisms of action cannot be ruled out. Lactoferrin also displays anti-parasitic activity, although the molecular mechanisms of such activity are even more complex.

The molecular structures, properties and energies of a molecule are better understood through the use of the “mechanical” molecular model. This model involves the development of a simple molecular mechanics energy equation representing the sum of various energy interaction terms comprised of bonds, angles, torsions of bonded, as well as, nonbonded atoms. Referred to as “force fields”, the model serves as a simple “descriptor” for vibrations in molecules. The concept of force fields is now widely employed as one of the simplest tools in molecular modeling. Force fields are fundamentally important in de novo drug design programs, in pharmacophore mapping, and represent the “scoring functions” in many docking programs. As scoring functions, force fields are used to rank “ligand poses” obtained by a docking algorithm, or in de novo ligand design programs to suggest placement of fragments in sites in the enzyme with the highest binding affinity. In all these applications, force fields are mainly used to compute the interaction energy between the protein and the ligand as pair-wise interaction potentials consisting of van der Waals and electrostatic interactions, in addition to H-bond energy between the ligand and the enzyme. Some examples of drug design software where force fields have been implemented as scoring functions are AMBER, GOLD AutoDock and DOCK. Force fields also play an important role in Free Energy perturbations (FEP) calculations that allow the design of newer analogs or inhibitors with an accurate prediction of their activity. This review will provide a historical overview including a discussion of the valence force field, the Urey-Bradley force field (UBFF), and the more recent Class II force fields such as Allinger's MM2-MM4, Accelrys CFF91 and others that apply to a large class of molecules. The GROMOS force field will also be discussed since it takes into consideration the free energies of hydration and the non-polar solvation for a range of compounds. This approach takes into account the relative free enthalpy of solvation between polar and non-polar environments, which is a key property in many biomolecular processes of interest including protein folding, biomolecular association, membrane formation and transport. The review will also focus on the current status of force fields in the study of ligand-protein interactions with particular emphasis on applicability in structure-based drug design.

Endophthalmitis is an eye inflammation, involving the vitreous cavity and its surrounding tissues responsible for vision. In most cases, an infection triggers this inflammation. The infection can be caused by bacteria, fungi, viruses or parasites. The occurrence of this severe and devastating inflammation can be related to surgical procedures, penetrating ocular trauma, and endogenous infections. Post-operative endophthalmitis represents the most frequent event accounting for more than 70% of cases. They are schematically divided in three categories: i. acute-onset endophthalmitis (within few days from surgery); ii. delayed-onset endophthalmitis or chronic endophthalmitis (one month to years after surgery); iii. endophthalmitis related to glaucoma filtration surgery, bleb-associated endophthalmitis. This complication has been reported after both surgery breaking up the ocular integrity and external eye surgery. In the former group, secondary intraocular lens placement and pars plana vitrectomy are associated with the highest and lowest endophthalmitis rate, respectively. Because cataract surgery is the most frequently performed intraocular surgery, the 90% of post-operative endophthalmitis occurs after this surgical procedure. Clinical signs of post-operative endophthalmitis are variable in relation to the typology of the infecting agent, the level of the intraocular inflammation, and the duration of the disease. Its clinical diagnosis should be followed by the collection and culturing of aqueous and vitreous specimens; in fact, because the results of these cultures are often negative and positive, respectively, is essential to obtain specimens from both anterior and posterior ocular chambers for a proper clinical management of each patient. In the majority of cases, the infective agents of a post-operative endophthalmitis cannot be identified without any doubt, but several evidences indicate that the bacterial flora of eyelids and/or conjunctiva is the most common cause of this complication. Contaminated solutions and instruments, surgeon and operating-room personnel represent other potential sources of infection. In absence of a specific infectious condition, such as conjunctivitis, dacryocystitis and blepharitis (which should be diagnosed and treated before any intraocular surgery), the pre-operative administration of antibiotics has not been shown to reduce the incidence and/or the severity of post-operative bacterial endophthalmitis. On the contrary, numerous studies have documented that the pre-surgical application of povidone-iodine to skin and conjunctiva effectively downgrades endophthalmitis frequency. The Endophthalmitis Vitrectomy Study (EVS) has investigated about the management of post-operative endophthalmitis, considering the roles of pars plana vitrectomy and systemic antibiotics in addition to standard treatments with intravitreal antibiotic and topical or systemic corticosteroids. It demonstrated that immediate pars plana vitrectomy was beneficial for patients with very low residual vision, whereas systemic antibiotics had no effect on visual outcome or media clarity. Although EVS remains the major randomized study regarding this topic, there are some weak-points which leave its conclusions open to future modifications. Particularly, in the EVS cluster: i. the fourth-generation fluoroquinolones - characterized by a better efficacy profile in comparison with ceftazidime and amikacin - have been not tested; ii. only cases of acute-onset endophthalmitis - typically caused by coagulase-negative micrococci - were enrolled, resulting in a lack of data about the delayed-onset and bleb-associated endophthalmitis. For these reasons, the EVS outcomes should not be generalized to all forms of endophthalmitis, which could potentially benefit utilizing different or additional therapeutic approaches.