Shao-Lin Zhang

Selective degradation of mitochondrial proteins remains a significant challenge due to the unique compartmentalization and proteostasis mechanisms of this organelle. Here, we report A1, a mitochondria-targeted small-molecule degrader that selectively eliminates pyruvate dehydrogenase kinases (PDKs) by recruiting the mitochondrial protease HsClpP, achieving nanomolar degradation potency (DC₅0 ≈ 10 nM). Mechanistically, A1 induces efficient pan-PDK degradation, thereby rewiring mitochondrial metabolism toward enhanced oxidative phosphorylation. This metabolic shift promotes the accumulation of reactive oxygen species (ROS), leading to opening of the mitochondrial permeability transition pore (mPTP) and activation of the intrinsic mitochondrial apoptosis. Notably, A1 also elicits hallmark features of immunogenic cell death (ICD), including calreticulin exposure and HMGB1 release, thereby stimulating antitumor immune responses. Consistent with these findings, A1 markedly suppresses both primary and distal tumor growth, with selective PDK degradation in tumor tissues and no observable systemic toxicity. Collectively, these results establish mitochondria-targeted degradation of metabolic enzymes as a promising therapeutic strategy for cancer.

This work performed a unique conjugation of metronidazole with berberine via thiazolidinedione to afford a novel structural skeleton of metronidazolyl vinylthiazolidionyl tetrahydroberberines (MVTs) with multitargeting antibacterial potential to conquer bacterial resistance. Most of the prepared MVTs exhibited an effective activity against most of the tested bacteria. Notably, butyl MVT 7b (MIC = 0.005 mM) demonstrated the strongest antibacterial activity against S. aureus 25923, being 3- and 69-fold more active than norfloxacin and berberine, respectively. Low hemolysis, cytotoxicity, and drug resistance, effective biofilm eradication, and efficient transport by human serum albumin suggested the favorable druggability of MVT 7b. Highly active MVT 7b could cause bacterial death through multitargeting effects, including disrupting the bacterial membrane, triggering oxidative stress, and intercalating into DNA without cleaving DNA. Moreover, MVT 7b was more potent than norfloxacin in vivo against S. aureus 25923. These medicinal chemobiological investigations demonstrated MVTs as potential multitargeting antibacterial candidates for alleviating bacterial resistance.

Simultaneous targeting of glycolysis and oxidative phosphorylation (OXPHOS) is an effective strategy for overcoming the metabolic plasticity of pancreatic ductal adenocarcinoma (PDAC). In this study, we present compound 14c, a rationally designed, mitochondria-targeted small molecule that disrupts PDAC energy metabolism. Compound 14c markedly inhibited PDAC cell glycolysis and mitochondrial function, as evidenced by the PDKs inhibition and the downregulation of OXPHOS-associated proteins, including SDHB and SIRT3, in vitro and in vivo. Mechanistically, 14c induced ferroptotic cell death, accompanied by lipid peroxidation, redox imbalance, and mitochondrial dysfunction. Importantly, 14c also elicited hallmarks of immunogenic cell death (ICD), including calreticulin exposure and HMGB1 release. In a syngeneic PANC02 model, 14c suppressed tumor growth with minimal systemic toxicity and recapitulated the metabolic inhibition and ICD-associated phenotypes observed in vitro. These findings support that 14c could be used as a dual metabolic inhibitor and ICD inducer in PDAC therapy.

The diversity of chemically synthesized scaffolds provides the channel for discovering antibacterial agents with novel structures or targets to conquer microbial resistance. This work developed a unique type of novel benzopyridonyl cyanovinylpyrimidines (BCPs). Most of BCPs gave high and broad-spectrum antibacterial activity; especially, amino BCP 31f and methylthio BCP 44a exhibited higher bacteriostatic potency (MICs = 0.25–1 μg/mL) against Staphylococcus aureus strains than ciprofloxacin. Low hemolysis, cytotoxicity, drug resistance, good plasma stability, and rapid bactericidal effects revealed their development potential. Mechanism research showed that active BCPs could intercalate into DNA to form a DNA-BCP supramolecular complex that might block DNA replication, inhibit the production of staphyloxanthin, and be effectively transported by human serum albumin. Moreover, amino BCP 31f displayed superior anti-MRSA efficacy to vancomycin in vivo. This series of medicinal chemobiological evaluation implied the great potential of novel benzopyridonyl cyanovinylpyrimidines as broad-spectrum antibacterial members to combat drug resistance.