Synthetic peptides have been used as model compounds to understand the biophysical tendencies of regions of soluble and membrane proteins. Our laboratories have utilized peptide surrogates of regions of HIV-1 to learn about the interaction of the envelope protein with neutralizing antibodies and with the HIV-1 co-receptor CCR5 and to develop knowledge that can be used in the design of therapeutics and peptide-based vaccines to treat AIDS. We have used HIV-1 V3-loop peptides as surrogates to study the bound structure of V3 to anti-HIV-1 antibodies. These investigations revealed a beta-hairpin structure in this loop of gp120. This knowledge permitted the design of disulfide constrained peptides that were engineered to assume the structure of V3 bound to the human broadly neutralizing antibody 447-52D. Immunization with the synthetic constrained peptides resulted in anti-sera that were effective in neutralizing Tier 1 and some Tier 2 HIV-1 strains. In recent work a 27-residue peptide surrogate of the N-terminus of the CCR5 chemokine co-receptor for R5 strains of HIV-1 containing two sulfotyrosine residues and ECL2 loop peptide mimetics were synthesized and used together with a synthetic soluble CD4 surrogate to map the regions of CCR5, ECL2 and gp120 that interact. The resulting ~45 KDa complexes were studied by high-resolution heteronuclear NMR spectroscopy. Detailed information about contact points was revealed and new hydrophobic clusters on gp120 that interact with the receptor are being defined. Our results provide novel insights into the structural biology of the ternary complex formed by gp120, CD4 and CCR5 and should be useful in the development of anti-HIV-1 therapeutics.