title: Quantitative analysis of the effect of zidovudine, efavirenz, and ritonavir on insulin aggregation by multivariate curve resolution alternating least squares of infrared spectra.
abstract: Quantification of the effect of antiretroviral drugs on the insulin aggregation process is an important area of research due to the serious metabolic diseases observed in AIDS patients after prolonged treatment with these drugs. In this work, multivariate curve resolution alternating least squares (MCR-ALS) was applied to infrared monitoring of the insulin aggregation process in the presence of three antiretroviral drugs to quantify their effect. To evidence concentration dependence in this process, mixtures at two different insulin:drug molar ratios were used. The interaction between insulin and each drug was analysed by (1)H NMR spectroscopy. In all cases, the aggregation process was monitored during 45 min by infrared spectroscopy. The aggregates were further characterised by scanning electron microscopy (SEM). MCR-ALS provided the spectral and concentration profiles of the different insulin-drug conformations that are involved in the process. Their feasible band boundaries were calculated using the MCR-BANDS methodology. The kinetic profiles describe the aggregation pathway and the spectral profiles characterise the conformations involved. The retrieved results show that each of the three drugs modifies insulin conformation in a different way, promoting the formation of aggregates. Ritonavir shows the strongest promotion of aggregation, followed by efavirenz and zidovudine. In the studied concentration range, concentration dependence was only observed for zidovudine, with shorter aggregation time obtained as the amount of zidovudine increased. This factor also affected the aggregation pathway.
authors.affiliation: Analytical and Organic Chemistry Department, Universitat Rovira i Virgili, Campus Sescelades, 43007 Tarragona, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: Martí-Aluja
authors.forename: Itziar
authors.initials: I
authors.lastname: Ruisánchez
authors.forename: M Soledad
authors.initials: MS
authors.lastname: Larrechi
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000032:analysis*; D048588:Benzoxazines / Q000032:analysis*; D003521:Cyclopropanes; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D016018:Least-Squares Analysis; D009682:Magnetic Resonance Spectroscopy; D008855:Microscopy, Electron, Scanning; D019438:Ritonavir / Q000032:analysis*; D013055:Spectrophotometry, Infrared; D015215:Zidovudine / Q000032:analysis*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D007328:Insulin; D015215:Zidovudine; C098320:efavirenz; D019438:Ritonavir