This project builds on the successful design and construction of the protein molecule known as AOP-RANTES. This was the first, nanomolar antagonist of the entry of M-tropic strains of HIV into the macrophage, a key event in the initiation of infection in humans. AOP-RANTES is an antagonist of a number of the chemokine receptors that are used by these viruses to gain entry into the cell. The purpose now is to develop this work further, in using the techniques of protein semi-synthesis and the total chemical synthesis of proteins to produce a large number of new, rationally designed, receptor antagonists of various types. These materials will be distributed to other investigators in the Program for (depending on the interests of the research workers concerned) screening, evaluation in vitro and in laboratory animals, and in selected cases, tests in humans. The molecules to be constructed will fall into five categories. 1. Molecules will be sought that are yet more potent antagonists of the receptors targeted by the M-tropic strains of the virus. 2. Molecules will be designed and constructed in an attempt to antagonize the receptor or receptors used by the T-tropic strains of the virus. 3. Variants will be constructed which will remain available in the circulation for longer periods. 4. Changes will be introduced into selected antagonists in an attempt to make them antagonize either a narrower or a wider range of the co-receptors used by HIV. 5. Other molecules will be constructed to serve as experimental reagents for basic research into HIV infection. These will principally be fluorescent and photo-activatable forms. Since chemical and not recombinant, techniques are to be used for the constructions, virtually the full range of organic chemical groups can be inserted at will to make, rapidly, milligram quantities of the construction. There is no limitation to the substitutions allowed by the genetic code. Data from the screening and evaluation of the first compounds will be used to drive further cycles of rational design and construction.
