Hui Cai

Pulmonary fibrosis (PF) is a life-threatening interstitial lung disease, which progressively impairs pulmonary function, with limited therapeutic options available. In this study, we designed CQ7, a self-assembling peptide that integrates a therapeutic peptide with a self-assembly motif. CQ7 monomers spontaneously form supramolecular nanofibers under physiological conditions, both extracellularly and intracellularly. This nanofiber structure promotes efficient lung retention and targeted pulmonary delivery, leading to enhanced anti-fibrotic efficacy. We evaluated the anti-fibrotic and anti-inflammatory effects of CQ7 in a murine PF model via both intraperitoneal and inhalation administrations. Transcriptomic sequencing and experimental validation further revealed that CQ7 may act through the regulation of mitochondrial function, reducing cellular oxidative stress and thereby regulating the apoptosis process. Collectively, this work demonstrates a novel peptide-based strategy with significant potential for improving PF outcomes and clinical translation.

We report a Zn(II)-mediated stereocontrolled galactosylation with two conformationally restricted GalN3 donors that enables divergent α- and β-glycosylation. The 4,6-O-TIPDS/3-O-Bz donor selectively affords α-GalN3 glycosides, while the 4,6-O-benzylidene/3-O-TIPS donor provides β-glycosides with high stereoselectivity. The methods show a broad substrate scope, good yields, and scalability and enable synthesis of GalNAc-α-Ser and the Acinetobacter baumannii CPS K45 tetrasaccharide repeating unit.

Diabetes mellitus poses a significant and escalating burden on global public health. As a major breakthrough in glycemic control, sodium-glucose transporters (SGLT) inhibitors are now established as indispensable agents for managing type 2 diabetes. This status is evidenced by the continuously increasing market share in the antidiabetic agent market worldwide. The development of these inhibitors shows how leads from natural products ultimately evolved into clinically useful agents via structure-based drug design. Specifically, structural modifications to overcome the metabolic instability of phlorizin have yielded orally administrable SGLT inhibitors with improved pharmacokinetic profiles. This modification represents a shift towards more resource-efficient and sustainable molecular design. In recent years, these inhibitors have been found to have cardiorenal protective effects independent of glycemic status in clinical trials, thereby fundamentally altering their therapeutic positioning towards heart failure and chronic kidney disease. This article reviews the current market landscape and the evolutionary trajectory of SGLT inhibitors. Additionally, we discuss emerging R&D strategies, highlighting the role of computational drug design and structural biology in accelerating the identification of novel scaffolds. By leveraging these advanced methodologies, researchers can overcome current limitations in potency and selectivity. These approaches offer promising avenues for optimizing lead compounds and developing next-generation therapies with improved pharmacological profiles.

Diabetes mellitus poses a significant and escalating burden on global public health. As a major breakthrough in glycemic control, sodium-glucose transporters (SGLT) inhibitors are now established as indispensable agents for managing type 2 diabetes. This status is evidenced by the continuously increasing market share in the antidiabetic agent market worldwide. The development of these inhibitors shows how leads from natural products ultimately evolved into clinically useful agents via structure-based drug design. Specifically, structural modifications to overcome the metabolic instability of phlorizin have yielded orally administrable SGLT inhibitors with improved pharmacokinetic profiles. This modification represents a shift towards more resource-efficient and sustainable molecular design. In recent years, these inhibitors have been found to have cardiorenal protective effects independent of glycemic status in clinical trials, thereby fundamentally altering their therapeutic positioning towards heart failure and chronic kidney disease. This article reviews the current market landscape and the evolutionary trajectory of SGLT inhibitors. Additionally, we discuss emerging R&D strategies, highlighting the role of computational drug design and structural biology in accelerating the identification of novel scaffolds. By leveraging these advanced methodologies, researchers can overcome current limitations in potency and selectivity. These approaches offer promising avenues for optimizing lead compounds and developing next-generation therapies with improved pharmacological profiles.

Despite the biological significance of stereodefined phenolic O-glycosides, their efficient synthesis remains challenging. Here, we report the stereoselective O-furanosylation of phenols toward bench-stable glycosyl fluorides by cooperative activation of a Lewis acid and transition-metal complex, proceeding in high yields at room temperature. The novel glycosylation strategy is demonstrated to be effective for a wide substrate scope of acceptors, including small molecules, natural products, and commercial drugs. Mechanistic studies, supported by TEMPO-trapping and DFT simulations, established a radical-mediated pathway for this glycosylation. To demonstrate the utility of this strategy for bioactive molecule diversification, we focused on phenolic compounds with known anti-inflammatory properties (e.g., sesamol). Their ribofuranose conjugates were synthesized and evaluated, leading to the discovery that glycosylation could potentiate the parent compounds’ ability to inhibit IL-6 production in LPS-stimulated macrophages, thereby demonstrating the potential of this glycosylation strategy to improve the pharmacological profiles of bioactive phenols.

Substituent functionalization of unprotected and partially protected carbohydrates with controlled regioselectivity remains challenging due to the difficulty in differentiating hydroxyl groups with similar reactivities. This study presents an efficient protocol for site-specific modification through a “two-stage,” regiodivergent polyol tagging and functionalization strategy. To achieve effective tagging, we developed two complementary Ag₂CO₃-ligand-based regimes that enable the regioselective sulfonylation of cis-diol and trans-diol in carbohydrates, controlled by simply toggling the presence of a [Pd] catalyst. Competition experiments and DFT simulations elucidated the underlying dual mechanisms accounting for the regioselectivity. [Pd] catalyst complexes to cis-diol as a bidentate ligand, enhancing the differentiated electrophilicities through stereoelectronic effects and preferentially activating the equatorial C3-OH groups. Conversely, without [Pd], the Ag­(I) complex switches the reaction position, directing sulfonylation to the axial hydroxyl within 1,2-cis-diol, a position that is typically kinetically inert under conventional conditions. And the Ag­(I) complex preferentially coordinates to cis-1,2-substituents on the sugar ring and selectively activates the C2-OH group. The sulfonylated products serve as versatile synthons for the following structural derivations and chemical glycosylations, facilitating efficient access to structurally unique rare sugars, deoxy- and aminosugar analogues, and complex oligosaccharides. This dual-catalytic approach provides a robust platform for precision carbohydrate engineering, advancing the synthesis of biologically relevant oligosaccharides and glycoconjugates.

Aberrantly glycosylated membrane proteins represent promising targets for cancer immunotherapy. However, glycan diversity and heterogeneity pose a challenge to developing effective vaccines against tumors expressing different glycoantigens. To broaden the immune response and enhance the vaccine’s efficacy by targeting a wide variety of glycosylation patterns on tumor cells, herein we developed a Mosaic glycopeptide vaccine by simultaneously presenting three different glycopeptides on the carrier protein tetanus toxoid (TT). Immunological evaluation revealed that the Mosaic vaccine elicited higher antibody titers than single-glycopeptide formulations, primarily mediating tumor cell lysis via antibody-dependent cellular cytotoxicity (ADCC) and significantly suppressing tumor growth in both wild-type and transgenic murine models. Notably, the Mosaic vaccine exhibited not only preventive but also therapeutic effects, demonstrating clear antitumor activity in transgenic mice. Combination therapy with PD-1 blockade further enhanced antitumor efficacy. In-depth mechanistic studies demonstrated that the Mosaic vaccine effectively activated antigen-presenting cells and T cells. Furthermore, serum antibodies from Mosaic vaccine-immunized mice exhibited selective binding to patient-derived pancreatic tumor tissues, suggesting their clinical translational potential.