Designing peptide-based drugs to target the beta-sheet-rich toxic intermediates during the aggregation of amyloid-beta 1-42 (A beta(1-42)) has been a major challenge. In general, beta-sheet breaker peptides (BSBPs) are designed to complement the enthalpic interactions with the aggregating protein, and entropic effects are usually ignored. Here, we have developed a conformationally constrained cyclic BSBP by the use of an unnatural amino acid and a disulfide bond. We show that our peptide strongly inhibits the aggregation of A beta(1-42) in a concentration-dependent manner. It stabilizes the random coil conformation of A beta(1-42) monomers and inhibits the secondary structural transition to a beta-sheet-rich conformation which allows A beta(1-42) to oligomerize in an ordered assembly during its aggregation. Our cyclic peptide also rescues the toxicity of soluble aggregates of A beta(1-42) toward neuronal cells. However, it significantly loses its potency in the conformationally relaxed acyclic form. It appears that limiting the loss of conformational entropy of the BSBP ligand can play a very important role in the attainment of conformations for precise and tight binding, making them a potent inhibitor for A beta(1-42) amyloidosis.