A 6.5-kb intergenic structural variation enhances P450-mediated resistance to pyrethroids in malaria vectors lowering bed net efficacy
Authors: Mugenzi, Leon M. J.; Menze, Benjamin D.; Tchouakui, Magellan; Wondji, Murielle J.; Irving, Helen; Tchoupo, Micareme; Hearn, Jack; Weedall, Gareth D.; Riveron, Jacob M.; Cho-Ngwa, Fidelis; Wondji, Charles S.
Elucidating the complex evolutionary armory that mosquitoes deploy against insecticides is crucial to maintain the effectiveness of insecticide-based interventions. Here, we deciphered the role of a 6.5-kb structural variation (SV) in driving cytochrome P450-mediated pyrethroid resistance in the malaria vector,Anopheles funestus. Whole-genome pooled sequencing detected an intergenic 6.5-kb SV between duplicated CYP6P9a/b P450s in pyrethroid-resistant mosquitoes through a translocation event. Promoter analysis revealed a 17.5-fold higher activity (p < .0001) for the SV- carrying fragment than the SV- free one. Quantitative real-time PCR expression profiling ofCYP6P9a/bfor each SV genotype supported its role as an enhancer because SV+/SV+ homozygote mosquitoes had a significantly greater expression for both genes than heterozygotes SV+/SV- (1.7- to 2-fold) and homozygotes SV-/SV- (4-to 5-fold). Designing a PCR assay revealed a strong association between this SV and pyrethroid resistance (SV+/SV+ vs. SV-/SV-; odds ratio [OR] = 2,079.4,p < .001). The 6.5-kb SV is present at high frequency in southern Africa (80%-100%) but absent in East/Central/West Africa. Experimental hut trials revealed that homozygote SV mosquitoes had a significantly greater chance to survive exposure to pyrethroid-treated nets (OR 27.7;p < .0001) and to blood feed than susceptible mosquitoes. Furthermore, mosquitoes homozygote-resistant at the three loci (SV+/CYP6P9a_R/CYP6P9b_R) exhibited a higher resistance level, leading to a far superior ability to survive exposure to nets than those homozygotes susceptible at the three loci, revealing a strong additive effect. This study highlights the important role of structural variations in the development of insecticide resistance in malaria vectors and their detrimental impact on the effectiveness of pyrethroid-based nets.
DFT and docking studies of designed conjugates of noscapines & repurposing drugs: promising inhibitors of main protease of SARS-CoV-2 and falcipan-2
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Authors: Kumar, Ajay; Kumar, Durgesh; Kumar, Ravinder; Singh, Prashant; Chandra, Ramesh; Kumari, Kamlesh
First case of the present epidemic, coronavirus disease (COVID-19) is reported in the Wuhan, a city of the China and all the countries throughout the world are being affected. COVID-19 is named by World Health Organization and it stands for coronavirus disease-19. As on 27(th) October, 2020, 73,776,588 people around the world are infected. It is also known as SARS-CoV-2 infection. Till date, there is no promising drug or vaccine available in market to cure from this lethal infection. As the literature reported that noscapine a promising candidate to cure from malaria as well reported to be cough suppressant and anti-cancerous. In our previous work, a derivative of noscapine has shown potential behavior against the main protease of novel coronavirus or SARS-CoV-2. Based on the previous study, hybrid molecules based on noscapine and repurposing (antiviral) drugs were designed to target the main protease of novel coronavirus and falcipan-2 using molecular docking. It is proposed that the designed hydrids or conjugates may have promising antiviral property i.e. against the main protease of novel coronavirus and falcipan-2. The designed molecules were thoroughly studied by DFT and different thermodynamic parameters were determined. Further, infrared and Raman spectra of the designed hybrid molecules were determined and studied. Communicated by Ramaswamy H. Sarma