Effect of carbohydrates on structure and function of glycopeptides
Summary of Research:
In general, protein glycosylation is a ubiquitous post-translational modification capable of transforming protein’s properties in different ways. It is known that glycosylation can profoundly impact a protein’s folding, stability, and intracellular trafficking. The structures and dynamics of several glycosylated peptides have been elucidated and it has been shown that peptide conformation is stabilized and its fluctuations restricted by the glycosylation. However, a detailed understanding of the functions of glycoproteins is often hindered by the structural microheterogeneity caused by the diverse patterns of glycosylation. The issues related to biological function of glycoproteins/glycopeptides can be evaluated, provided suitable quantities of rational model systems can be made available. The chemical syntheses of homogenous glycopeptides have allowed generating a diverse array of carbohydrate structures for studying their functions and local perturbations in a systematic fashion. Our research specifically focuses on understanding the differential roles of carbohydrates domains using synthetic glycoconjugates involving the model system such as:
Antimicrobial glycopeptides of innate immune origin : The resistance of insects to bacterial infection is explained by their ability to synthesize a diverse range of antibacterial peptides. A remarkable feature of some proline rich antibacterial peptides such as drosocin, pyrrhocoricin, formaecins, diptericin and lebocins which have been isolated from insects, is the presence of conserved O-glycosylated threonine residue and the integrity of the carbohydrate side chain is necessary for their maximum activity. The exact role of the sugar remains an enigma. We are addressing the problem of role of carbohydrate domains in the activity of antimicrobial glycopeptides by studying their structure-function relationship. However, the mode of action of this class of cationic antimicrobial glycopeptides is not known completely and they are thought to kill bacteria by entering cells and binding to target/targets. The studies addressing mechanistic aspects are also undertaken and are in progress for the isolation and characterization of the bacterial target proteins.
Novel glycopeptide inhibitors of thrombin : Thrombin is a serine protease which has central role in maintaining haemostasis. However, the physiological effects of this protease are far more than expected, ranging from blood coagulation to cell cycle regulation, inflammation, pregnancy etc. Thrombin is the central player in a wide number of pathologies like coagulation related disorders, cancer, blood born infections etc. Hence thrombin has been a potential drug target for decades. Several inhibitors have been developed against thrombin since then. We are aiming for designing a fast acting, highly specific and potent thrombin inhibitory glycopeptide. Our specific aim includes the synthesis of various designed glycopeptide inhibitors of thrombin and their structure-function relationship studies.
Deepti Sripad Lele, PRV Shabareesh, Sushma Nagpal, H S Sarna, Nihal Singh