Although loop epitopes at protein-protein binding interfaces often play key roles in mediating oligomer formation and interaction specificity, their binding sites are underexplored as drug targets owing to their high flexibility, relatively few hot spots, and solvent accessibility. Prior attempts to develop molecules that mimic loop epitopes to disrupt protein oligomers have had limited success. In this study, we used structure-based approaches to design and optimize cyclic-constrained peptides based on loop epitopes at the human phosphoglycerate dehydrogenase (PHGDH) dimer interface, which is an obligate homo-dimer with activity strongly dependent on the oligomeric state. The experimental validations showed that these cyclic peptides inhibit PHGDH activity by directly binding to the dimer interface and disrupting the obligate homo-oligomer formation. Our results demonstrate that loop epitope derived cyclic peptides with rationally designed affinity-enhancing substitutions can modulate obligate protein homo-oligomers, which can be used to design peptide inhibitors for other seemingly intractable oligomeric proteins.