Liquid-phase peptide synthesis (LPPS) has emerged as a powerful platform for constructing complex peptide natural products, yet its efficiency remains highly dependent on carrier design, protecting group compatibility, and late-stage functional group manipulations. Here, we report a streamlined LPPS strategy enabled by a benzoyl-type tag carrier that facilitated tert-butoxycarbonyl (Boc)-based elongation, mild carrier cleavage, and direct access to C-terminal peptide alcohols. This platform enabled the concise synthesis of kozupeptin aldehyde—an exceptionally potent antimalarial peptide aldehyde—in only 11 purification steps from commercially available methyl gallate, representing a substantial improvement over previous methodologies. The robustness of the benzoyl tag system further allowed the rapid preparation of 10 analogs by parallel one-pot LPPS via single-residue scanning across the peptidic core. Biological evaluation against Plasmodium falciparum revealed tight structure–activity relationships, identifying strict sequence and conformational requirements for potency while highlighting the crucial stereoelectronic influence of the 4-methyl-proline (Pro(4-Me)) residue and the threonine (Thr)–proline (Pro) amide bond equilibrium. Collectively, this work establishes a versatile LPPS approach for accelerated access to peptide natural products and provides new insights into the conformational determinants underlying kozupeptin’s antimalarial activity.
Sennari et al. (Mon,) studied this question.