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Disulfide-rich peptides (DRPs) are a class of peptides that are constrained through two or more disulfide bonds. Though natural DRPs have been extensively exploited for developing protein binders or potential therapeutics, their synthesis and re-engineering to bind new targets are not straightforward due to difficulties in handling the disulfide pairing problem. Rationally designed DRPs with an intrinsically orthogonal disulfide pairing propensity provide an alternative to the natural scaffolds for developing functional DRPs. Herein we re