RESEARCH

Understanding the Disease Pathogenesis and Drug Design

Neurodegenerative diseases like Alzheimer’s, Parkinson’s or Huntington’s disease have a debilitating effect on the patient’s day-to-day life. Accumulation and aggregation of misfolded proteins, either resulting from a severe stress response or due to failure in cellular clearance pathway for misfolded proteins in the process of aging, are found to play a central role in the formation of plaques observed in patients’ brains. The undesired protein aggregation is also prominent in other diseases including auto-immune diseases like rheumatoid arthritis and type II diabetes mellitus which affects close to 500 million people world wide. In our lab we try to understand the mechanistic details of protein aggregation by investigating both the kinetics and thermodynamics of the processes that drive the protein conformational change and the fibril formation. A thorough understanding of the mechanism will ultimately enable us in developing inhibitors to retard and prohibit the production of toxic aggregates.

Design of Drug Delivery Carriers

 Efficacy of treatment is not assured by the discovery of an effective drug. It is necessary to ensure that the drug is available at the right quantity at the right location. The extent of the aqueous solubility and the membrane permeability of a drug determine its bioavailability. A good fraction of drug molecules being hydrophobic in nature have poor solubility. Entrapping such a drug within the hydrophobic pocket of a stable nanostructure that has a hydrophilic exterior is a typical strategy to enhance the drug bioavailability due to high solubility of the drug-carrier complex. Such a nanostructure is called a drug delivery carrier, it also helps in controlled and sustained release of the drug. Conjugation of cell-specific receptors on the carrier could help in targeted drug delivery i.e., drug release only to the specific site of action, especially important in cancer treatment. We are keen in computationally designing stable drug delivery carriers made of natural polymers like peptide or oligosaccharides that are biodegradable. On the basis of the underlying molecular interactions we predict the best molecular packing that determines the shape and stability of the carrier and the drug-carrier complex. We also investigate the extent of solubility enhancement and how the nanocarriers facilitate drug transport across the biomembranes.

Assessing and Enhancing Therapeutics Stability

Protein based therapeutics have been gaining popularity in recent years, for example, antibody therapy for cancer. One of the major challenges faced by pharmaceutical industries in manufacturing them, especially at high therapeutic concentration, is how to prevent agglomeration and precipitation of biomolecules that would drastically impact the product quality and its shelf life, especially in the countries with poor cold-chain management. Unwarranted agglomeration and precipitation could also lead to low therapeutic efficacy and undesired immunogenic responses. Excipients are typically added to increase the stability and shelf life of the therapeutics. The identification of such excipients and the complete drug formulation, however, is usually carried out through a time-consuming trial and error method. We are keen in developing a strategic process of identifying the excipient and the drug formulation from the investigation of molecular level interactions that drive the protein agglomeration. We also explore the relevance of conjugation of glycan and short biocompatible polymers like PEG in enhancing the stability of bio-therapeutics.