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Document Page 517 than the wild-type virus. At the optimal drug concentration for growth, the pH-stability of these mutations is equivalent to that of native HRV1A in the absence of drug. Increasing drug concentration beyond that which is optimal for growth further increases the acid-stability of these mutant viruses so that they are more acid-stable than native virus without drug (Daniel Pevear, personal communication). C. Clinical Resistance and Virulence The clinical importance of these mutations has not been clearly demonstrated. In at least one case a drugresistant mutant was able to grow in vitro in single-cycle growth experiments as well as wild-type HRV14 [28]. Frequently, however, drug-resistant or acid-stable mutants will not grow as well in cell culture as native virus [93]. The final analysis of the clinical importance of resistant mutants awaits the results of clinical trails. In the one study published to date, HRV2 mutants of the compensation type (resistant to the capsid-binding compound chalcone) were tested in healthy human volunteers [65]. The drug-resistant mutants caused significantly fewer colds than the normal virus. Mutants that require the presence of drug to grow did not cause any apparent disease. In this single case it appears that the mutant viruses were not as virulent as the parent strain. VI. Animal and Clinical Studies The idea that an inhibitor that binds to a nonenzymatic, nonreceptor site of a virion could inhibit viral replication in vivo would a priori be considered to be an unlikely scenario by most in the field of structure-based design. If this idea were proposed knowing only the structure of the native virus (especially HRV14, which has a closed-pocket conformation) skepticism would abound. This type of project arose not from a structure-based approach, but from the tried-and-true screening approach. The compounds were first shown to be effective in inhibiting viral replication in vitro [52]. This was followed by an experiment showing that these compounds could inhibit at least one enterovirus in a mouse model [94]. In this study, suckling mice were inoculated with an echovirus and if untreated they developed a fatal paralytic illness. When treated either prophylactically or within a few days of the viral inoculation, virtually all of the mice were protected. This is dramatic proof of the concept that these compounds can inhibit picornaviral infection in vivo. There are important differences between mice and men and between enteroviral paralytic illness and rhinoviral upper respiratory tract infections. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_517.html [4/9/2004 12:45:48 AM]
Document Page 518 The differences between mice and men should be obvious to the casual reader. Enterovirus-induced paralytic illnesses are systemic infections, and the virus must at some point move through the body and be subject to circulating drug. Upper respiratory infections resulting from rhino-or enteroviruses tend to be localized to the pharynx, which would require that drug titers remain high in this region of the body. In spite of these difficulties, there have been some dramatic successes in clinical trials of antirhinovirals, although clearly there are still obstacles to overcome. Two different classes of antipicornavirus compounds have been shown to be successful at inhibiting at least some types of infection when administered prophylactically. The WIN compound 54954, given orally, has been shown to inhibit Coxsackie virus A21 in humans [6]. The Jaansen compound R77975 has been shown to inhibit HRV9 when administered intranasally 6 times daily [95,96], but R77975 has not been shown to inhibit infection when used therapeutically (after symptoms occur). Further clinical trials with WIN 54954 were suspended due to the developments of side effects. More recently VP 63843 has been shown to have dramatically improved effect when compared with WIN 54954 in the prophylactic treatment of Coxsackie virus A21 infection in humans and it will be tested therapeutically. The inability of R77975 to show a therapeutic effect is more likely due to poor pharmacodynamics rather than a fundamental inability for this compound to inhibit an established infection. The pharmacodynamic problem was witnessed in the R77975 study, which showed that administration intranasally 3 times a day did not yield prophylactic protection. Yet if administered 6 times daily the prophylaxis occurs. Therefore if more potent and metabolically stable compounds are found, more positive clinical results would be expected. VII. Future Directions The structures of the picornaviruses (native, with receptor bound, in the presence of acid, with a myriad of compounds bound, and of acid- and drug-resistant mutants) have yielded valuable information about possible molecular mechanisms for their uncoating. These same studies have suggested the mechanism by which these uncoating inhibitors work. A by-product of this research is the hypothesis that these compounds may mimic naturally occurring factors that occupy the VP1 pocket. The hunt for these natural compounds and their significance is underway. This understanding of the mechanism of action, as well as the structure-activity studies, have also yielded valuable information for future development of antipicornaviral drugs. The determination of compound's size, shape, and other physical requirements for activity will also be of assistance. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_518.html [4/9/2004 12:45:50 AM]
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