Design, synthesis, and evaluation of carboxyl-modified oseltamivir derivatives with improved lipophilicity as neuraminidase inhibitors

Wang, Boyu; Wang, Kuanglei; Meng, Peipei; Hu, Yaping; Yang, Fei; Liu, Kemin; Lei, Zaiqiang; Chen, Binfeng; Tian, Yuan

doi:10.1016/j.bmcl.2018.09.014

Cited by 14 publications

(5 citation statements)

References 21 publications

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“…The so-called 4-methylumbelli-feryl N-acetyl-α-D-neuraminic acid (MUNANA, a fluorogenic NA substrate) or NA-STAR (a chemiluminescent NA substrate) assays allow to quantify the hydrolysis of a small soluble substrate by NA. The small molecule NA inhibitor oseltamivir, which binds precisely inside the catalytic site, inhibits NA activity in these types of assays ( 97 ). Only a mAb that binds inside or in very close proximity to the catalytic site will be able to prevent cleavage of the small substrate whereas mAbs that bind distal to the catalytic site are less likely to have an effect in such assays.…”

Section: Neuraminidase-specific Monoclonal Antibodies: Mechanisms Of Action and Epitopesmentioning

confidence: 99%

Influenza Neuraminidase Characteristics and Potential as a Vaccine Target

et al. 2021

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Neuraminidase of influenza A and B viruses plays a critical role in the virus life cycle and is an important target of the host immune system. Here, we highlight the current understanding of influenza neuraminidase structure, function, antigenicity, immunogenicity, and immune protective potential. Neuraminidase inhibiting antibodies have been recognized as correlates of protection against disease caused by natural or experimental influenza A virus infection in humans. In the past years, we have witnessed an increasing interest in the use of influenza neuraminidase to improve the protective potential of currently used influenza vaccines. A number of well-characterized influenza neuraminidase-specific monoclonal antibodies have been described recently, most of which can protect in experimental challenge models by inhibiting the neuraminidase activity or by Fc receptor-dependent mechanisms. The relative instability of the neuraminidase poses a challenge for protein-based antigen design. We critically review the different solutions that have been proposed to solve this problem, ranging from the inclusion of stabilizing heterologous tetramerizing zippers to the introduction of inter-protomer stabilizing mutations. Computationally engineered neuraminidase antigens have been generated that offer broad, within subtype protection in animal challenge models. We also provide an overview of modern vaccine technology platforms that are compatible with the induction of robust neuraminidase-specific immune responses. In the near future, we will likely see the implementation of influenza vaccines that confront the influenza virus with a double punch: targeting both the hemagglutinin and the neuraminidase.

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Section: Neuraminidase-specific Monoclonal Antibodies: Mechanisms Of Action and Epitopesmentioning

confidence: 99%

Influenza Neuraminidase Characteristics and Potential as a Vaccine Target

et al. 2021

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“…Aliquots were sampled at 0, 5, 10, 20, 30 and 60 min incubation, and enzymatic reaction was stopped by protein precipitation in cold acetonitrile including 100 ng/mL tolbutamide and 100 ng/mL labetalol as internal standard. After centrifugation, samples were then analyzed by LC/MS/MS [26].…”

Section: Methodsmentioning

confidence: 99%

Evolution and Antibacterial Evaluation of 8-Hydroxy-cycloberberine Derivatives as a Novel Family of Antibacterial Agents Against MRSA

Yang

Wei

et al. 2019

Molecules

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Twenty-five new derivatives of 8-hydroxycycloberberine (1) were synthesized and evaluated for their activities against Gram-positive bacteria, taking 1 as the lead. Part of them displayed satisfactory antibacterial activities against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-intermediate Staphylococcus aureus (VISA). Especially, compound 15a displayed an excellent anti-MRSA activity with MICs (minimum inhibitory concentrations) of 0.25–0.5 μg/mL, better than that of 1. It also displayed high stability in liver microsomes and whole blood, and the LD50 value of over 65.6 mg·kg−1 in mice via intravenous route, suggesting a good druglike feature. The mode of action showed that 15a could effectively suppress topo IV-mediated decatenation activity at the concentration of 7.5 μg/mL, through binding a different active pocket of bacterial topo IV from quinolones. Taken together, the derivatives of 1 constituted a promising kind of anti-MRSA agents with a unique chemical scaffold and a specific biological mechanism, and compound 15a has been chosen for the next investigation.

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“…The OSMIP@silica gel column displayed good affinity and selectivity for template OS and peramivir, and hence, it could be employed to search more active neuraminidase inhibitor analogues from traditional herbs. Li and co-workers 104 have studied the inhibitory activities of a series of carboxyl-modified oseltamivir analogs against neuraminidase from H5N1 virus. One compound has shown potent inhibitory activity (IC 50 = 1.30 ± 0.23 μM) and is more lipophilic (log D = −0.12) than oseltamivir carboxylate (log D = −1.69) at pH of 7.4.…”

Section: Neuraminidase Inhibitors (Nais)mentioning

confidence: 99%