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Document Page 513 broad spectrum activity (Table 8) [56,90]. While certain less-flexible compounds may have increased potency for a particular serotype of HRV, these compounds have lower potency versus other serotypes. It is not known if the effect of flexibility is an equilibrium or kinetic effect. The flexibility might allow the compounds to expand or contract to fill available space in the VP1 hydrophobic pocket. Alternatively, the flexibility may allow the compounds to achieve a conformation required to enter or leave the pocket, but this conformation would not be seen in the crystallographic experiment. If this is true, modeling of the equilibrium structure of compounds in the pocket will not be accurate predictors of compound potency. Structure—Activity Relationship Summary The combination of classical structure—activity relationships combine with the structures of several compounds in a number of HRV serotypes have led to a paradigm for designing potent compounds. The effects of pocket shape, requirements for hydrophobicity in the toe of the pocket, as well as the potential for hydrogen bonding in the heel region appear to be strong determinants of antiviral potency. The requirement for a broad spectrum has so far limited a more detailed paradigm, such as one that might exist for designing inhibitors to a specific serine protease. In spite of this vagueness of antirhinoviral structure—activity relationships, they have been useful in guiding new compound synthe- http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_513.html [4/9/2004 12:44:57 AM]
Document Page 514 sis. Large numbers of compounds, which might have been synthesized in the absence of any structural knowledge, have been eliminated from the list of inhibitors to be created, because these compounds would not have fit well into the VP1 pocket due to its finite size and hydrophobic nature. The goal of being able to predict with greater accuracy the potency and spectrum of compounds before they are synthesized awaits three developments: the structures of more HRVs and compounds, the ability to more accurately model hydrophobic interactions, and probably the most difficult, the ability to predict changes in the HRVs that occur due to drug binding. V. Viral Resistance As would be expected for any virus, particularly an RNA virus, resistance to capsid-binding compounds has been observed in the laboratory. The effect such mutations have on the life cycle of the virus is important. Mutations that occur in regions where changes are poorly tolerated, because that region serves a vital function in the viral life cycle, are likely to lead to less virulent viruses. The almost universal inhibition of rhino- and enteroviruses by capsid-binding compounds, coupled with the observation that all of the viruses with determined structures have a VP1 hydrophobic pocket, suggests that these pockets serve an important and similar function. It seems unlikely that so many viruses would maintain such a pocket if it were not a selective advantage. Drug-resistance mutants have been classified into two groups, exclusion mutants and compensation mutants. A. Exclusion Mutants The exclusion mutants' behavior has been readily and adequately determined by biochemical and crystallographic means [91,92]. The mutations occur within the hydrophobic pocket of VP1 and thermostabilization studies have shown that these mutations preclude the binding of drug in the VP1 pocket. One mutation site in HRV14 has been located at position 1188, which is on the side of the pocket closest to the viral interior, away from the canyon. Mutations at this site that convey resistance are Val rarrow.gif Leu or Val rarrow.gif Met. In both cases the mutation is to a larger side chain, which would be expected to fill the pocket. The crystal structure of the Val rarrow.gif Leu mutation confirms this hypothesis and demonstrates that the Leu side chain occupies space that would normally be occupied by an antiviral drug. The second site found in HRV14 is at Cys1199. Mutations to Phe, Tyr, Trp, and Arg all confer resistance at this site. Again, all of these mutations are to larger side chains. The hypothesis that these mutations function by excluding http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_514.html [4/9/2004 12:45:35 AM]
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