Nikkomycin Z

Aspergillosis is one of the most common fungal infections that can threaten individuals with immune compromised condition. Due to the increasing resistance of pathogens to the existing antifungal drugs, it is difficult to tackle such disease conditions. Whereas, nikkomycin is an emerging safe and effective antifungal drug which causes fungal cell wall disruption by inhibiting chitin synthase. Hence, the study aims at the development of nikkomycin loaded PEG coated PLGA nanoparticles for its increased antifungal efficiency and inhibiting Aspergillus infections. The P-PLGA-Nik NPs were synthesized by w/o/w double emulsification method which resulted in a particle size of 208.3 ± 15 nm with a drug loading of 52.97 %. The NPs showed first order diffusion-controlled drug release which was sustained for 24 h. These nanoparticle’s antifungal efficacy was tested using the CLSI – M61 guidelines and the MIC50 defined against Aspergillus flavus and Aspergillus fumigatus was found to be >32 μg/ml which was similar to the nikkomycin MIC. The hyphal tip bursting showed the fungal cell wall disruption. The non-cytotoxic and non-haemolytic nature highlights the drug safety profile.

NF-kappaB-Inducing Kinase (NIK) is a key kinase in the activation of the NF-κB non-classical signalling pathway, which has been shown to be over-activated in patients with inflammatory diseases, immune disorders and malignancies and solid tumours inducing activation of the NF-κB non-classical signalling pathway. The design of ATP-competitive small molecule inhibitors against NIK has been a hot topic in the last decade, and many efficient NIK inhibitors have been identified. In this work, I aim to unravel the mechanism of NIK inhibition by different representative NIK type I 1/2 kinase inhibitors, using ADME, molecular docking, molecular dynamics simulation, MM-PBSA analysis and 3D-QSAR analysis. This work contributes to the understanding of the efficiency of NIK inhibitor binding by revealing the basis of the efficiency of NIK inhibitors, the difference in binding modes between different inhibitors and the overall effect on NIK.Communicated by Ramaswamy H. Sarma.