The transmembrane protein gp130 acts as the signal transducing receptor subunit for interleukin-6 type cytokines, including viral interleukin-6, which is encoded by the Kaposi's sarcoma-associated herpes virus. Viral interleukin-6 has been shown to mimic human IL-6 functions, including activation of the JAK1 and STAT1/3 signaling pathways. Based on the crystal structure of three extracellular domains of gp130 in complex with viral interleukin-6, we have designed and synthesized a range of assembled peptides that mimic the sequentially discontinuous binding site of gp130 for viral interleukin-6. These peptides, which present the three binding site fragments of gp130 in a nonlinear, discontinuous fashion, were shown to inhibit the interaction of gp130 with viral interleukin-6, as well as the stimulation of viral interleukin-6-induced cell proliferation. These results validate the concept of synthetic mimicry of discontinuous protein-binding sites through assembled peptides, and the use of such molecules as modulators of protein-ligand interactions.