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.

The development of selective inducers of extracellular or membrane protein degradation has attracted attention as next-generation drugs. Herein, we report a novel lysosome-targeting chimera (LYTAC) comprising a fusion protein (G67-(GGGGS)_n-IGF2), in which insulin-like growth factor 2 (IGF2) is linked to an Fc-binding peptide derived from protein G (G67) via several repeats of a GGGGS linker (n = 0–3). G67-(GGGGS)_n-IGF2 forms non-covalent complexes with the Fc region of the Fc domain–containing proteins. The trastuzumab-based human epidermal growth factor receptor 2 (HER2) targeting Fc-LYTAC (FcL-2) markedly induced HER2 degradation. The HER2 degradation activity of FcL-2 was inhibited by the inhibition of lysosomal activities, indicating that Fc-LYTAC induces target protein degradation via the endocytosis-lysosomal pathway. The Fc-LYTAC methodology could be extended to epidermal growth factor receptor–binding antibodies and even Fc-tagged HER2-binding single-chain variable fragments. These results provide an innovative strategy for the conversion of membrane protein–binding molecules with an Fc region into efficient target protein degradation inducers.

Synthetic studies toward the indole diterpene penitrem E are described. A functionalized o-alkynylaniline derivative was designed as a model substrate to construct the D/E/F/G tetracyclic core bearing an exocyclic functional group on the F ring as a precursor for C₁₈ oxygen installation. The tetracyclic compound is furnished through a Pd-catalyzed cascade cyclization of the o-alkynylaniline derivative, which involves indole formation, an intramolecular Heck reaction, and oxidative chlorination of the Heck intermediate.

2,3,4,5-Tetrahydro-1,5-benzoxazepine derivatives constitute an important class of heterocycles frequently found in pharmaceuticals. In this study, we developed an efficient and practical synthetic method for the construction of 2,3,4,5-tetrahydro-1,5-benzoxazepine cores starting from N-aryl isoxazolidines. The key step involves Lewis acid–mediated alkoxy migration induced by N–O bond cleavage using aluminum chloride, providing the desired heterocyclic scaffolds in good yields. This method offers a new route to access 2,3,4,5-tetrahydro-1,5-benzoxazepine frameworks and expands the utility of N-aryl isoxazolidines in heterocycle synthesis.

Cell-penetrating peptides (CPPs) have attracted considerable attention as carriers that facilitate the intracellular delivery of biomacromolecules. In this study, the amphipathic antimicrobial peptide K9L9 was used as a model, and a series of peptides incorporating the non-proteinogenic amino acid α-aminoisobutyric acid (Aib) were designed and synthesized to investigate the relationship between peptide structure, membrane interaction, and cellular uptake behavior. Circular dichroism analysis revealed that K9L9 adopted a β-sheet–like conformation in an aqueous solution, whereas the Aib-containing peptide formed a stable α-helical structure. In liposome leakage assays, peptides containing two Aib residues exhibited enhanced membrane-disruptive activity, whereas the peptide containing four Aib residues exhibited reduced activity. Furthermore, intracellular delivery studies using fluorescein isothiocyanate-dextran (FITC-dextran) demonstrated that delivery efficiency was significantly enhanced when the peptides were preincubated with FITC-dextran, suggesting that peptide–cargo complex formation plays a critical role in the delivery process. In addition, K9L9 exhibited rapid cellular uptake at early time points, whereas the Aib-containing peptides showed a gradual increase in uptake over time, indicating distinct uptake kinetics. These results demonstrate that Aib-induced helix stabilization modulates the membrane interaction and cellular uptake behavior of amphipathic peptides.