Design and Synthesis of Beta-Hairpin Peptidomimetics for Modulating Integrin Mediated Cell Adhesion, Abeta Fibrillogenesis and p53-MDM2 Protein-Protein Interactions

Inhibiting therapeutically important protein-protein interactions has been a tremendous challenge for medicinal chemists. The folded 3D structures of peptides and proteins, mainly comprise secondary structural elements i.e α-helices and β-sheet have created an opportunity to design small molecules and peptidomimetic inhibitors of protein-protein interaction (PPI). Hence, information about the formation and stabilization of these secondary structures is vital for designing future drugs. In this dissertation, several cyclic beta-hairpin peptidomimetics that mimic the recognition surface have been designed and synthesized as inhibitors for different targets such as integrin mediated extracellular matrix -cell adhesion in multiple myeloma, p53-MDM2 PPI, amyloid beta fibrillogenesis inhibitor. Cyclization of linear peptides to restrict the number of conformations available to the linear peptide can increase its affinity for the target as well as increase its proteolytic resistance. In this study, different beta turn promoters that increase the propensity of cyclic peptides to adopt beta-sheet structures have been designed and synthesized. Chapter two discusses the design and synthesis of several cyclic III (Integrin Interaction Inhibitor) peptides that block adhesion of integrins to extracellular matrix components in Multiple Myeloma tumor cells. These cyclic peptides, as assayed by TOPRO 3 assay were more potent than the parent linear peptide with a bio-activity of 1.08 μM. We have also studied structure activity relationships (SAR) of these cyclic III peptide analogs to increase the potency and bioavailability of these peptides. Chapter three describes the application of cyclic beta-hairpin peptidomimetics to inhibit abeta fibrillogenesis that is responsible for Alzheimer’s disease. We have successfully designed and synthesized cyclic peptides that target the hydrophobic region (17-21) of abeta fibril which is believed to cause self aggregation and plaque formation. We have also successfully explored these cyclic beta-hairpin peptides to disrupt p53-MDM2 interactions. Chapter five discusses the design and synthesis of novel cysteine based Peptide Nucleic Acid (PNA) monomers that are aimed to increase cellular uptake by introducing positively charged species attached to the cysteine side chain. We have successfully synthesized CPNA monomers and made efforts to make PNA oligomers

Integrin interaction inhibitors for the treatment of cancer

Integrin interaction inhibitors using a beta-turn promoter are described herein. These peptides are useful in treating cancer, such as multiple myeloma, by administering a therapeutically effective amount of the integrin interaction inhibitor. Data show that integrin interaction inhibitors act synergistically or additively interact with anti-proliferative agents such as doxorubicin, SAHA, arsenic trioxide, and etoposide

Integrin interaction inhibitors for the treatment of cancer

Integrin interaction inhibitors using a beta-turn promoter are described herein. These peptides are useful in treating cancer, such as multiple myeloma, by administering a therapeutically effective amount of the integrin interaction inhibitor. Data show that integrin interaction inhibitors act synergistically or additively interact with anti-proliferative agents such as doxorubicin, SAHA, arsenic trioxide, and etoposide

Oral health-related knowledge, attitude and practices among eunuchs (hijras) residing in Bhopal City, Madhya Pradesh, India: A cross-sectional questionnaire survey

Background: The current cross-sectional questionnaire survey was conducted to assess the oral health-related knowledge, attitude and practices among eunuchs (hijras) residing in Bhopal city, Madhya Pradesh, India. Materials and Methods: Based on a convenient non-probability snow ball sampling technique, all the self-identified eunuchs residing in the city of Bhopal who were present at the time of study and who fulfilled the selection criteria were approached. A cross section of the general population was also surveyed. An interviewer-based, predesigned, structured, close-ended 18-item questionnaire that had been designed based on the primary objective of the study was used. All the obtained data were analyzed using software, Statistical Package for Social Science version 20. Results: According to 188 (86.2%) males, 187 (87.4%) females and 168 (81.2%) eunuchs, good oral health can improve the general health. Most of the study participants including 211 (98.6%) females, 210 (96.3%) males and 205 (99%) eunuchs use either tooth paste or tooth powder to clean their teeth. While, a majority of eunuchs, i.e., 113 (54.6%), were having habit of chewing smokeless tobacco containing products such as betel nut, betel quid, gutkha, etc., The difference in use of tobacco products was statistically significant. Conclusion: The information presented in this study adds to our understanding of the common oral hygiene practices which are performed among eunuch population. Efforts to increase the awareness of oral effects of tobacco use and to eliminate the habit are needed to improve oral and general health of this population

Sensitive and Quantitative Detection of Anti-Poly(ethylene glycol) (PEG) Antibodies by Methoxy-PEG-Coated Surface Plasmon Resonance Sensors

Pre-existing and induced anti-poly­(ethylene glycol) (PEG) antibodies (abs) have been shown to be related with limitation of therapeutic efficacy and reduction in tolerance of several therapeutic agents. However, the current methods to detect anti-PEG abs are tedious and usually lack quantification. A facile, rapid, sensitive, and reliable technique to detect anti-PEG abs is highly desired in both research and clinic settings. In this work, we have presented a surface plasmon resonance (SPR) biosensor technique for the detection of anti-PEG abs and compared three PEG surface chemistries. Methoxy-PEG (mPEG) 5k was found to have the best performance. The detection of anti-PEG abs directly from diluted blood serum was achieved within 40 min. Detection sensitivity is as good as or better than enzyme-linked immunosorbent assay (ELISA). Furthermore, different antibody isotypes can be quantitatively differentiated by adopting secondary antibodies. A pilot study has been performed to analyze clinical blood samples using this technology, demonstrating its potential as a convenient and powerful method to prescreen and monitor anti-PEG abs in the patients before or after they receive treatment with PEG-containing drugs