The shell-structure of several picornaviruses (human rhinoviruses 1A and 14 and of types 1 and 3 poliovirus), have been solved to atomic resolution. Thus it is now possible to literally "see" (with the aid of computer imaging) the position of drugs in the virus shell, the shape of the drug binding site, and the effect of drug-resistance mutations, within the structure of the shell. Human rhinoviruses are the most important single cause of the common cold (40% of colds in adults), but the large number of serotypes (100) has effectively precluded the use of vaccines. Now, however, a number of promising rhinovirus-neutralizing compounds have been developed by several corporations. Moreover the receptor for 90% of known rhinoviruses has been identified as intercellular adhesion molecule I (ICAM-1), which has already been cloned and is available in purified form. This unique combination of experimental information makes human rhinoviruses key models for studies on the molecular design of neutralizing antivirals and for unraveling the molecular details of virus attachment and uncoating. We here propose to strengthen ongoing collaborative work with Rossmann's team of X-ray crystallographers at Purdue University and with the research team at Sterling Drug in Rensselaer, NY. A long-range goal of our work is to define the structural and genetic basis of antiviral drugs and receptors which block attachment or uncoating of human picornaviruses. Specific emphasis will be devoted to studies of: (1) human picornavirus 14 (HRV14) as a model for studying attachment inhibitors (WIN drugs and soluble ICAM-1); and (2) type 3 poliovirus as a model for locating resistance mutations to RNA-uncoating using the uncoating inhibitor WIN 5171 1. We have developed a molecular cDNA clone of HRV 14 which makes RNA transcripts 80-90% as infectious as virion RNA; the insights gained from mapping spontaneous drug-resistance mutations have helped focus which regions are most profitably explored for constructing new mutations in the virus. We also propose exploratory studies with human rhinovirus 16 (HRV16) which we believe might open the way for development of a model system to study pathways to, and consequences of, drug resistance by RNA viruses in man.