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The development of vaginal microbicides for the prevention of sexual transmission of HIV is becoming an increasingly important strategy in the battle against the AIDS epidemic. Several first generation microbicide candidates are entering Phase III efficacy trials, and several other candidates are in earlier stages of clinical development. The capacity to make accurate clinical assessments of the safety and efficacy of microbicide formulations is critical. Since microbicide trials will rely on a blinded, randomized, placebo-controlled design, it is important to employ a placebo formulation that does not distort either safety or efficacy assessments. Efficacy of the microbicide would be underestimated if the placebo itself provided a degree of protection. Conversely, a placebo with epithelial toxicity that increased susceptibility would cause an overestimation of microbicide efficacy. To address these issues, a hydroxyethylcellulose (HEC) placebo formulation has been developed and has been adopted for use in clinical evaluations of investigational microbicides as a "universal" placebo. In this report, the chemical and physical properties of this formulation are described, as well as its in vitro and in vivo effects on safety and efficacy. The results show that this "universal" placebo has adequate physical properties, is sufficiently stable as a vaginal gel formulation, and is safe and sufficiently inactive for use in the clinical study of investigational microbicides.

The focus of the 17th International Conference on Antiviral Research was the discovery and development of antiviral agents (chemistry, biology, animal models and clinical trial results) against a variety of human infectious agents including HIV, herpes viruses, hepatitis viruses, respiratory viruses and emerging/re-emerging pathogens. The meeting included the symposium ‘Clinical Update on Antiviral Drugs’, plenary sessions dedicated to each of the individual classes of infectious agents, a symposium on new developments surrounding emerging pathogens, and three special award lectures, which discussed the history of nucleotide antiviral agents, mechanisms of viral persistence and drug resistance, and the therapy of herpes virus infections. Within each infectious agent session the presentations included those describing the development of new and novel anti-infectives, including research based on the preclinical development of new molecules, and the results of animal modelling and clinical studies on advanced-stage antiviral agents. A summary of the meeting highlights, segregated by infectious agent, will be presented in this review.

A new series of cosalane analogues incorporating two fragments of the dichlorodisalicylmethane pharmacophore has been synthesized. In order to identify the position for the attachment of the pharmacophore fragments to the steroid ring that results in the most potent analogues, two types of compounds were designed. In the first type, the two pharmacophore fragments were attached at C-3 and C-17 of the steroid ring by using appropriate linker units. In the second type, both pharmacophore groups were connected to C-3 of the steroid through an alkenyl chain containing an amide moiety. All of the new compounds displayed antiviral activity versus HIV-1RF, HIV-1IIIB, and HIV-2RODin cell culture. The relative potencies of the compounds resulting from the two attachment strategies were found to depend on the viral strain as well as the cell type. Overall, the attachment of the second pharmacophore did not result in either a large gain or a large loss in anti-HIV activity, and the results are therefore consistent with the hypothesis that the two pharmacophores act independently, and one at a time, with positively charged amino acid side chains present on the surface of gp120 and CD4.

Plant-derived and semi-synthetic calanolide compounds with anti-human immunodeficiency virus type 1 (HIV-1) activity were tested for anti-human cytomegalovirus (HCMV) activity in both cytopathic effect inhibition and plaque reduction assays. The results indicated that the anti-HCMV activity of calanolide compounds does not correlate with their activity against HIV-1. The semi-synthetic 12-keto derivatives tended to be more active against HCMV than the corresponding 12-OH congeners, which were more active against HIV-1. It appeared that the 7,8-unsaturated double bond in the chromene ring played a certain role in maintaining activities against both HCMV and HIV-1. Saturation of the double bond increased the EC50values against both viruses, with concomitant increase in toxicity. The calanolide compounds reported here are the first non-nucleoside analogues capable of inhibiting both HIV-1 and HCMV and, therefore, may be useful chemoprophylactic agents for HCMV in HIV-infected people or vice versa.

Introduction of an amido group or an amino moiety into the alkenyl linker chain of cosalane (1) provided a new series of analogues 3–8. The new compounds were evaluated as inhibitors of the cytopathic effect of HIV-1 and HIV-2 in cell culture. The replacement of the 1′ and 2′ carbons in the linker chain of 1by an amido group was generally tolerated. The length of the linker chain and the stereochemistry of the substituent at C-3 of the steroidal ring had significant effects on the antiviral activity and potency. Incorporation of an amino moiety into the linker completely abolished the anti-HIV activity. There are several steps in the HIV replication cycle that have been proposed as targets for the development of therapeutic agents (De Clercq, E. J. Med. Chem.1995, 38, 2491; De Clercq, E. Pure Appl. Chem.1998, 70, 567). However, currently approved anti-HIV drugs are only directed against the viral enzymes reverse transcriptase or protease (Carpenter, C. C. J.; Fischl, M. A.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S. G.; Richman, D. D.; Saag, M. S.; Schooley, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.; Volberding, P. A. JAMA1998, 280, 78). Drugs capable of interfering with other steps of the virus life cycle will be highly valuable in the antiretroviral therapy of AIDS, as they will have different patterns of resistance mutations than the drugs currently used clinically. In addition, their utilization in combination with other therapeutic agents could provide more potent drug ‘cocktails’ capable of completely suppressing virus replication. Consequently, there is an urgent need for the discovery of clinically useful anti-HIV agents possessing novel mechanisms of action.

Coupling of 2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranosyl bromide with 4-methoxypyrazolo[3,4-d]pyrimidine gave an α-D/β-D mixture of N¹- and N²-coupled products. All the anomers were separated and deblocked to yield the corresponding nucleosides. The β-D-anomer 7 was converted to the 4-amino derivative 11, which was deaminated by adenosine deaminase to give the 4-oxo compound 12. Compound 7 showed significant activity against human cytomegalovirus and hepatitis B virus, and compound 11 showed activity against human herpes virus 8. All the compounds were noncytotoxic in several human tumor-cell lines in culture.

The ultimate goal of a preclinical development program for a potential anti-HIV agent must be to rapidly define the efficacy and toxicity of the candidate compound, as well as its range and mechanism of antiviral action, its activity in combination with other known anti-HIV drugs, and the relative rate at which it selects drug-resistant virus isolates. With this information, appropriate in vivo studies may be designed to further evaluate efficacy, drug metabolism, pharmacokinetics, and toxicity. In the absence of a well-defined animal model to evaluate anti-HIV efficacy in vivo, in vitro studies are of critical importance to the selection and prioritization of compounds for expedited development. A research and development program consisting of both cell-based and biochemical mechanism-based assays will be described which allows the rapid accumulation of data regarding the anti-HIV activity of a candidate compound required to judiciously select a compound likely to be effective in a clinical setting. This preclinical development program has been designed to address points to consider suggested by the Food and Drug Administration for new anti-HIV agents and to direct critical time and resources to the development of appropriate compounds.