Qingzhi Gao

Kasugamine (2,4-diamino-2,3,4,6-tetradeoxy-d-mannose, 1) is a rare multideoxy diamino-sugar forming the core skeleton of the commercial aminoglycoside antibiotic Kasugamycin (KSG, 2), an agricultural fungicide that has been used against rice blast disease for more than 60 years. Despite the reported biosynthetic gene cluster (BGC) for 2, the enzymatic logic leading to the formation of 1 remained unclear. Here, we report the biosynthetic mechanism of 1. Five enzymes─KsgQ, KsgB, KsgD, KsgR, and KsgC─can biochemically convert uridine diphosphate-N-acetyl-d-glucosamine (UDP-GlcNAc, 4) to generate the sugar donor 6, which is incorporated into 2, as confirmed by stable isotope-labeled feeding experiments. KsgB is characterized as the first enzyme catalyzing the deacetylation of uridine diphosphate-N-acetyl-d-mannosamine (UDP-ManNAc, 5), while KsgR represents the first UDP-sugar 3-dehydrase catalyzing the C-3 deoxygenation of the KsgD product (8) via the cofactors pyridoxal-5'-phosphate (PLP) and l-glutamic acid (l-Glu), and employs a ColD-like catalytic mechanism, as shown by crystallographic analysis, molecular docking, and site-directed mutagenesis. Our findings unravel the biosynthetic mysteries of 1, highlight the intriguing strategies for biosynthesizing diamino-sugars in nature, and provide some evidence for further completely uncovering the biosynthetic logic of 2.

The severe toxicity of podophyllotoxin and its analogs primarily constrains their clinical application. We designed and synthesized a series of novel podophyllotoxin derivatives that target tumor-specific transporters to enhance tumor selectivity and reduce systemic toxicity. Among the new analogs, B11 as a LAT1-targeted amino acid conjugate, exhibited significantly greater anticancer activity against Eca109 cells than etoposide and with an ideal druggability profile. B11 achieved a 64.6% TGI versus 30.6% for etoposide in mice bearing Eca109 xenografts in a single drug treatment. The MTD studies showed a more than 4-fold improvement for B11 in animal tolerability compared to etoposide. Pharmacokinetic experiments revealed that B11 can achieve a higher drug distribution in tumors and minimize drug concentration in vital organs. Mechanistic studies indicated that B11 could accumulate in tumor cells in a LAT1-dependent manner and exert its antitumor effects by cytoskeleton disruption.

Oxaliplatin-based chemotherapy has proven to be one of the most effective treatments for advanced or metastatic colorectal cancer. However, increasing clinical resistance to oxaliplatin poses unprecedented challenges for both patients and clinicians. Despite extensive efforts to combat this issue, to date, no new molecules have been discovered that can successfully replace oxaliplatin. With the aim of developing a new generation of Pt(II)-based anticancer agents in response to the challenges of oxaliplatin-induced drug resistance, we performed a systematic screening of new Pt(II)-complexes with a quantitative structure-activity relationship (QSAR) study based on their antiresistance activity against oxaliplatin-resistant colon cancer cells. The results revealed that both the structure and chirality of the chelating ligand had a significant impact on the antiresistance properties of the Pt(II)-complexes. Our study culminated in the identification of chiral R-binaphthyldiamine-ligated Pt(II)-malonatoglycoconjugates that can completely counteract oxaliplatin resistance with excellent in vitro and in vivo potency.

The artificially synthesized strigolactone (SL) analogue GR24 is currently the most widely used reference compound in studying the biological functions of SLs. To elucidate the structure-activity relationship and find more promising derivatives with unique molecular profiles, we design and synthesized three series of novel GR24 derivatives and explored their activities in hypocotyl and root development of Arabidopsis. Among the 50 synthesized compounds, A11a, A12a, and A20d were found to have high activities comparable to GR24 for hypocotyl and/or primary root elongation inhibition in Arabidopsis. Some new analogues have been discovered to exhibit unique activities: (1) A20c, A21e, and A21o are specific inhibitors in primary root elongation; (2) A21c, A26c, and A27a exhibit a high promotion effect on Arabidopsis primary root elongation; and (3) A27e possesses the most unique profiles completely opposite to GR24 that promotes both hypocotyl elongation and primary root development. Moreover, we revealed that the AtD14 receptor does not affect the inhibitory effect of SL analogues in Arabidopsis root development. The ligand-receptor interactions for the most representative analogues A11a and A27e were deciphered with a long time scale molecular dynamics simulation study, which provides the molecular basis of their distinct functions, and may help scientists design novel phytohormones.

The biomedical application of corannulene π‐bowls is historically limited by low solubility and bioavailability despite the potential in their unique electronic properties for new functional materials. Herein, the unexpected role and molecular mechanism of Corranulene π‐bowls are uncovered in biomedical applications as an effective anticancer agent for Warburg effect mediated selective tumor targeting. The corannulene triazolyl monosaccharides Cor‐sugars exhibit highly potent cytotoxicity against human cancer cells and effectively inhibit xenograft growth of hyperglycolytic tumors. Particularly, the galactose‐conjugated Cor‐gal exhibits superior in vivo anticancer efficacy in A549 tumor models with outstanding safety profile compared to doxorubicin. Moreover, the combined treatment of Cor‐gal with immune checkpoint inhibitor results in an effective synergy in treating H460 human lung carcinoma. An uptake mechanism study reveals that Cor‐sugars exploit tumor‐specific glucose transporter glucose transporter 1 (GLUT1) for targeted cell delivery and intra‐tumoral accumulation through the cancer‐specific Warburg effect. Their significant anticancer activity is attributed to multiphasic DNA‐binding and cell cycle alteration effects. This study uncovers new molecular properties of corannulene buckybowl and enabling their potential new applications in biomedical engineering.

新型冠状病毒肺炎（Corona Virus Disease 2019，COVID-19）因具有极强的传染力和无特效治疗药物，导致疫情在全球大规模传播。目前疫苗的接种和推广一定程度上缓解了COVID-19大流行，但从临床治疗角度仍需要行之有效的治疗手段和抗病毒药物才能阻止这种新型病毒对人类健康造成的巨大威胁。由于抗病毒新药的研制周期漫长，其研发过程涉及靶点的选择、体外药效筛选、体内药理学及毒理学验证以及临床安全性及治疗效果的确认等不同阶段才能最终获得具有临床应用价值的治疗药物。经过科研工作者的不懈努力，针对新型冠状病毒SARS-CoV-2的特异性靶点而设计和筛选的少数小分子新冠病毒抑制剂药物，目前已进入临床验证并取得了令人振奋的治疗效果。本文对疫情爆发以来的抗病毒热点药物尤其是对SARS-CoV-2具有潜在治疗作用的代表性抗病毒化合物，综述了其药学分类、作用靶点、药效机制以及相关的临床测试结果。基于抗新冠病毒药物的研发现状分析和总结，明确了药物研发人员在新冠肺炎疫情防治工作中肩负的责任和面临的挑战，提出研制能有效抑制病毒感染的新药研发方向。

A fluorescently labeled mono-glycoconjugated calix[4]arene, as a multifunctional molecular carrier possesses ability for Warburg effect mediated tumor diagnosis and GLUT1 targeted drug delivery.

We report a non-antibody GLUT1 inhibitor probe NBDQ that is 30 times more sensitive than the traditional GLUT1 transportable tracer for cancer cell imaging and Warburg effect-based tumor detection. NBDQ reveals significant advantages in terms of tumor selectivity, fluorescence stability and in vivo biocompatibility in xenograft tumor imaging, including triple-negative breast cancer.