The interaction of HIV with its receptor, CD4, and the activity of the HIV reverse transcriptase are both significant targets for antiviral drug design. (1) The structure of a gp120-binding fragment of CD4 has been determined, making it possible to propose a systematic series of experiments with CD4-based inhibitor design as the goal. The high- resolution structural information now available will be used to design constrained peptide and related compounds that might mimic the C"""""""" ridge of CD4 domain 1 (the interaction site for HIV-gp120). Compounds will be tested for inhibition of CD4 binding to gp120, and the conformations of interesting species will be studied by NMR. Certain mutants of CD4 (W62Y, S49V, G38A, L44S) that have lowered affinity for gp120 will be expressed and crystallized, in order to confirm or modify the interpretation of their effects. Understanding the basis for lowered affinity of these mutants is important for the constrained peptide design, because interpretation of the mutants has been significant for defining the synthetic problem. (2) Crystals of HIV-RT have been grown that diffract to at least 3.8 Angstroms resolution. They are in space group F222 (a = 166, b = 169, c = 640). The structure of RT in these crystals will be determined, using X-ray data collection at liquid nitrogen temperature on the F1 beamline at CHESS. Synthesis of specific template/primer complexes, mimicking the two sequence-specific steps in HIV replication by RT, is in progress, and efforts will be made to obtain appropriate co-crystals. The tRNA:primer- binding-site complex will also be studied in association with the nucleocapsid protein, p7.
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