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Research in the Ferracane Lab focuses on the design, synthesis, structural analysis, and evaluation of peptides and glycopeptides. It provides students interested in chemistry, biochemistry, medicine, or pharmacy with the opportunity to engage in meaningful research relevant to their interests. The majority of students gain employment or acceptance into graduate programs (MS/PhD, PharmD, MD) in their field of interest.
We are currently studying the structure-activity relationship of opioid peptides to develop better treatments for pain and/or addiction (Project 1). We also study O-glycoprotease enzymes and their ligands to better understand this enzyme family’s role in bacterial pathogenesis and potential use as research tools (Project 2). These projects have been supported by internal and external funding sources and have resulted in several peer-reviewed publications.
Project 1: Structure-Activity Relationship of Opioid Peptides
Project 1: Structure-Activity Relationship of Opioid Peptides
Figure 1. Backbone conformation of the cyclic tetrapeptide cyclo[Pro-Sar-Phe-D-Phe].
Project Summary:
Unlike most peptides, cyclic tetrapeptides possess proteolytic stability, oral bioavailability, and blood-brain barrier permeability that imparts the scaffold with drug-like properties. Cyclo[Pro-Sar-Phe-D-Phe] (Figure 1) is a potent opioid that has shown utility in treating pain and attenuating the rewarding effects of cocaine and morphine in mouse model systems. Thus, cyclo[Pro-Sar-Phe-D-Phe] and related peptides have potential to treat pain and/or addiction. We are working to better understand how these compounds exhibit this activity through systematic synthesis, conformational analysis, and in vitro/in vivo analysis.
Key Techniques:
Peptide Synthesis & Purification, PAMPA, HPLC, LCMS, NMR Spectroscopy, & Molecular Modeling
Ongoing Collaborations:
Jane Aldrich (University of Florida)
Jay McLaughlin (University of Florida)
Jose Rodriguez (UCLA)
Funding:
National Science Foundation
ACS Division of Organic Chemistry
Relevant Reading:
Brice-Tutt, A.; Wilson, L. L.; Eans, S. O.; Stacy, H. M.; Simons, C. A.; Simpson, G. G.; Coleman, J. S.; Ferracane, M. J.; Aldrich, J. V.; McLaughlin, J. P. Multifunctional Opioid Receptor Agonism and Antagonism by a Novel Macrocyclic Tetrapeptide Prevents Reinstatement of Morphine-Seeking Behavior. Br. J. Pharmacol. 2020, 177, 4209-4222 [link]
Ferracane. M. J.; Brice-Tutt, A. C.; Coleman, J. S.; Simpson, G. G.; Wilson, L. L.; Eans, S. O.; Stacy, H. M.; Murray, T. F.; McLaughlin, J. P.; Aldrich, J. V. Design, Synthesis, and Characterization of the Macrocyclic Tetrapeptide cyclo[Pro-Sar-Phe-D-Phe]: a Mixed Opioid Receptor Agonist-Antagonist Following Oral Administration. ACS Chem. Neurosci. 2020, 11, 1324-1336 [link]
Project 2: Investigation of O-Glycoprotease Enzymes and Their Ligands
Project 2: Investigation of O-Glycoprotease Enzymes and Their Ligands
Figure 2. Structure of a model glycopeptide (green and yellow) docked in the active site of an O-glycoprotease (gray).
Project Summary:
O-glycoproteases are a family of enzymes that cleave O-linked glycoproteins but not their unglycosylated analogs. Bacteria of the gut microbiome secrete these enzymes to access nutrients and evade the host immune system. Still, these enzymes are underexplored, as their potential role in infection and use as biochemical tools remains poorly understood. We have been involved in several efforts to investigate O-glycoproteases (StcE, CpaA, AM0627, and SmE) using molecular modeling to elucidate the details of enzyme-substrate recognition (Figure 2). We are using this insight to develop ligands that enable deeper study of O-glycoproteases.
Key Techniques:
Amino Acid & Glycopeptide Synthesis & Purification, HPLC, LCMS, & Molecular Modeling
Ongoing Collaborations:
Stacy Malaker (Yale University)
Relevant Reading:
Shon, D. J.; Kuo, A.; Ferracane, M. J.; Malaker, S. A. Classification, structural biology, and applications of mucin-targeting proteases. Biochem. J. 2021, 478, 1585-1603 [link]
Malaker, S. A.; Pedram, K.; Ferracane, M. J.; Bensing, B. A.; Krishnan, V.; Pett, C.; Yu, J.; Woods, E. C.; Kramer, J. R.; Westerlind, U.; Dorigo, O.; Bertozzi, C. R. The mucin-selective protease StcE enables molecular and functional analysis of human cancer-associated mucins. Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 7278-7287 [link]
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