The aim of the Project is to develop new cost-effective complement inhibitors.
There are clinically significant following problems in administration of Liposomal nanomedicines as noticeable adverse reactions occurs by activation of the immune system’s Complement. The interaction of the nanomaterials with complement system is inter-related in terms of size and surface characteristics.
Cholesterol within phospholipid bilayer can be recognized by C3/C5 convertase. This drives the activation of the complement.
The project utilizes microfluidic design, Green Chemistry and, in silico modelling, to improve the liposomal structure resulting in the reduction of the complement inhibition. The liposomes are tested using ELIZA assays to identify when cholesterol analogues achieve the reduction in the complement inhibition.
The Complement inhibitors are designed using various methodologies described below:
Green Synthesis: The activation of complement in an effective manner by Green Chemical Synthesis of Cholesterol and its analogues using Bio-catalysis by the various filamentous fungi. The bio-catalytic approach is used to minimize the multistep organic synthesis at low temperatures in absence of organic synthesis.
Preparation and Characterization of Liposomes: Liposomes are composed of DPPC with various concentrations of the cholesterol. They are prepared by hydrating the dried lipid film, extruded, and then Characterised using DSC, PCS, and TEM.
ELISA assay: The characterized Liposomes are tested using the ELISA assays to determine which formulations reduce complement.
Microfluidics: Microfluidics is used as a controlled platform for the generating the uniform and nano-sized crystals. This is achieved by using the Tandem microchannel reactor. The crystals are incorporated into the liposomes.
Molecular Dynamic Simulations for the optimization of the Cholesterol and its analogues using in silico forcefields: The in silico optimization of the cholesterol by atomistic models using GROMOS forcefield to study structural and dynamics properties of the cholesterol and its analogues in DPPC bilayers by using coarse-grained MARTINI forcefields.
The Study of the preferential interaction of C3 Convertase with lipid bilayers by multi-scale molecular dynamics simulation. This results in demonstrating how the C3 convertase is influencing within the lipid bilayers.
The dynamic properties of the C3 are studied using atomistic simulations.
The influential properties of the Cg simulation with DPPC and Cholesterol is studied using MARTINI models.
Haritha Isukapatla- Early Stage Researcher
Department of Pharmacy - University of Lincoln (UK)