Eastern Michigan University
direct edit

Deborah Heyl-Clegg, Ph.D.

Professor and Head

Dr. Deborah Heyl-Clegg 541C Mark Jefferson Bldg

734.487.2057

dheylcle@emich.edu

Education

A.B., Lafayette College
Ph.D., University of Michigan

Medicinal and Biochemistry

Interests and Expertise

As chemical messengers of biological information, peptides present a promising class of compounds in the preliminary stages of pharmaceutical development. Peptides are made by joining amino acids through amide bonds, giving rise to a flexible backbone with variable side chains. The large molecule is able to fold into many different three-dimensional shapes due to rotation about certain bonds; these conformations are stabilized by several molecular forces like hydrogen bonds, electrostatic attraction/repulsion, and hydrophobic interactions. The same forces are involved in attracting the peptide to its target receptor, fitting like a specific key in a lock. Often, only a few parts of the molecule are responsible for binding to a receptor to cause a physiological effect, while the rest of the molecule provides a structural framework which properly orients these critical functionalities. The rational design of peptide drugs is an iterative one involving a systematic removal or modification of individual amino acids, varying chemical and physical properties such as solubility, electronic character, and size and shape. This influences how the peptide can fold, which, in turn, determines its behavior. Through these structure-activity studies, the desired pharmacological action can be improved while enhancing selectivity, eliminating harmful side effects. Each peptide is designed, synthesized by solid phase peptide synthetic techniques, purified by high performance liquid chromatography, and tested for bioactivity via an appropriate specialized assay. EMU students are involved in all aspects of the work.

We have applied the SAR technique to several biologically active peptides. These include the development of: 1) non-addictive opiate analgesics based on deltorphin, 2) α-amylase enzyme inhibitors based on Tendamistat to control sugar levels in diabetes, 3) antimicrobial peptides based on LL-21 and Tachyplesin that destroy drug resistant bacteria, and 4) insulin-based inhibitors of pancreatic amyloid formation in Type II Diabetes by human islet amyloid polypeptide. Current projects are outlined below:

1 - Development of Antimicrobial and Anti-Cancer Peptides Because of the increasing resistance of bacteria to traditional antibiotics, peptides with antimicrobial activity are a promising alternative to traditional therapies. Tachyplesin is an antimicrobial peptide from horseshoe crab that exhibits anti-bacterial activity by destroying bacterial cell membranes. The positive charges of the arginine and lysine residues allow for specificity for the bacterial membranes, as they are attracted to negatively charged components in the cell membranes (mammalian membranes tend to contain more positively charged phospholipids). The hydrophobic part then allows for penetration of the lipid membrane. Attraction of membrane components to the peptides disrupts membrane structure, creating holes and leading to cell death. This mechanism of action is difficult to overcome; therefore, it is believed that bacteria would not be able to develop resistance to this class of antibiotic compounds. In our analogs, the Cys residues were removed, eliminating the ability to form rings and resulting in linear peptides, which is synthetically and economically advantageous. Certain residues have been substituted to lead to better interaction with the bacterial membrane. Some of our analogs show better selectivity for bacterial over mammalian cells than the original peptide (cysteine-deleted tachyplesin, or CDT).   Currently, we are investigating whether these peptides can also target and slow the growth of cancer cells in different cell lines.  This is accomplished by creating/synthesizing modified peptide analogs and testing them in MTT cell viability assays, Erk signaling cascades, and other analyses.

2 - Neuroscience projects: Using peptides to explore protein-protein interactions implicated in depression or Alzheimer's disease in vitro and in mammalian cells. In each case, the peptides are designed to mimic the sequence of a protein at the interface where it associates with another protein, whether it is an enzyme, hormone or receptor. The peptides are then assayed to determine whether they compete with the larger protein, disrupting the protein-protein interactions, coupling, or oligomerization. Structure-activity studies also can be performed by modifying the sequences (amino acid substitutions, shortening and lengthening sequences, etc.) to enhance the contacts between the peptides and the protein. Current targets include the neuroprotective peptide humanin and IGFBP3 or humanin and beta-amyloid (Alzheimer’s Disease), and the D1 and D2 dopamine receptors (depression).  After peptide design, synthesis and purification, assays often involve protein expression, cell culture and co-immunoprecipitations.  These projects are collaborative with other chemistry faculty members.

Publications

"D-Amino Acid Analogues of the Antimicrobial Peptide CDT Exhibit Anti-Cancer Properties in A549, a Human Lung Adenocarcinoma Cell Line" Hedeel Guy Evans, Jeffrey W. Guthrie, Murali Jujjavarapu, Nathan Hendrickson, Anna Eitel, Yeji Park, Jennifer Garvey, Rebecca Newman, Daniel Esckilsen, and Deborah L. Heyl (2017), Peptide and Protein Letters, 24, 590-598.

"Team-Based Learning, Faculty Research, and Grant Writing Brings Significant Learning Experiences to an Undergraduate Biochemistry Laboratory Course" Hedeel Guy Evans, Deborah L. Heyl, and Peggy Liggit (2016), Journal of Chemical Education, 93 (6), 1027–1033.

"Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3 (IGFBP3) and regulates its interaction with importin-β" Evert Njomen, Hedeel Guy Evans, Samanthi Herath Gedara and Deborah L. Heyl (2015), Peptide and Protein Letters, 22 (10), 869-876.

"Modified Cysteine-Deleted Tachyplesin (CDT) Analogs as Linear Antimicrobial Peptides: Influence of Chain Length, Positive Charge, and Hydrophobicity on Antimicrobial and Hemolytic Activity" Stacie J. Wood, Yeji A. Park, Naga Pooja Kanneganti, Hareesh Reddy Mukkisa, Lauren L. Crisman, Sarah E. Davis, James L. Vandenbosch, Jamie B. Scaglione, and Deborah L. Heyl (2014), International Journal of Peptide Research and Therapeutics, 20 (4) 519-530.

"Intersubunit Communication in the Dihydroorotase-Aspartate Transcarbamoylase Complex of Aquifex aeolicus" Hedeel Guy Evans, Roshini Fernando, Asmita Vaishnav, Mahalakshmi Kotichukkala, Deborah L. Heyl, Joseph S. Brunzelle, Brian F.P. Edwards, and David R. Evans (2014) Peptide Science, 23(1), 100-109.

"Membrane Disordering is not Sufficient for Membrane Permeabilization by Islet Amyloidogenic Polypeptide: Studies of IAPP (20-29) Fragment" Jeffrey R. Brender, Deborah L. Heyl, Shyamprasad Samisetti, Samuel A. Kotler, Joshua M. Osborne, Ranadheer R. Pesaru, and Ayyalusamy Ramamoorthy (2013) Physical Chemistry Chemical Physics, 15, 8908-8915.


"Modeling the interface between islet amyloid polypeptide and insulin-based aggregation inhibitors: Correlation to aggregation kinetics and membrane damage" Hector Figueroa, Durgaprasad Peddi, Joshua M. Osborne, Brenan M. Wilson, Ranadheer Reddy Pesaru, Balakrishna Kurva, Swathi Ramaraju, Maria C. Milletti, and Deborah L. Heyl (2012) Journal of Chemical Information and Modeling, 52, 1298-1307.

"Liposome Damage and Modeling of Fragments of Human Islet Amyloid Polypeptide (IAPP) Support a Two-Step Model of Membrane Destruction" Deborah L. Heyl, Joshua M. Osborne, Sarika Pamarthy, Shyamprasad Samisetti, Andrew W. Gray, Anitha Jayaprakash, Srikanth Konda, Dorothy J. Brown, Samuel R. Miller, Reza Eizadkhah, Maria C. Milletti (2010) International Journal of Peptide Research and Therapeutics, 16 (1), 43-.54.

"Antimicrobial and Membrane Disrupting Activities of a Peptide Derived from the Human Cathelicidin Antimicrobial Peptide LL-37" Sathiah Thennarasu, Anmin Tan, Rajesh Penumatchu, Charles E. Shelburne, Deborah L. Heyl and Ayyalusamy Ramamoorthy, (2010) Biophysical Journal, 98, 248-257.

"Variation of the pKa in the N-Terminal Tyrosine Side Chain in Octapeptide Analogs of Tendamistat Influences a-Amylase Inhibition" D.L. Heyl, B. Sethi, A. Rogalski, C.E. Bowen, M. Lawrence, L. Beitler, E. Harning, A. Hancer, S. Sreekumar and S. Fernandes, (2007) Protein and Peptide Letters, 14, 497-501

"Membrane Fragmentation by an Amyloidogenic Fragment of Human Islet Amyloid Polypeptide Detected by Solid-State NMR Spectroscopy of Membrane Nanotubes" Jeffrey R. Brender, Ulrich H.N. Durr , Deborah L. Heyl, Mahender B. Budarapu , Ayyalusamy Ramamoorthy, (2007) Biochim. Biophys. Acta., 1768, 2026-2029.

"Deletion of All Cysteines in Tachyplesin I Abolishes Hemolytic Activity and Retains Antimicrobial Activity and LPS Selective Binding" A. Ramamoorthy, S. Thennarasu, A. Tan, Kiran Gottipati, Sreeja Sreekumar, Deborah L. Heyl, F.Y.P.An and C.E. Shelburne, (2006) Biochemistry, 45, 6529-6540

"Correlation of LUMO Localization with the a-Amylase Inhibition Constant in a Tendamistat-Based Series of Linear and Cyclic Peptides", Deborah L. Heyl, Steve Fernandes, Leena Khullar, Jennifer Stephens, Elizabeth Blaney, Horacia Opang-Owusu, Benjamin Stahelin, Todd Pasko, Jana Jacobs, Danielle Bailey, Dennis Brown and Maria C. Milletti, (2005) Bioorganic & Medicinal Chemistry 13/13, 4262-4268.

"Peptide Inhibitors of a-Amylase Based on Tendamistat: Development of Analogues with w-Amino Acids Linking Critical Binding Segments", Deborah L. Heyl, Shakila Tobwala, Leo Solomon Lucas, A. Dammika Nandanie, Rebecca W. Himm, Jennifer Kappler, Elizabeth J. Blaney Jason Groom, Jeffrey Asbill, Jonathan K. Nzoma, Cara Jarosz, Hanna Palamma, and Stephen E. Schullery (2005) Protein and Peptide Letters, 12, 275-280.

"pKa and volume of residue one influence d/m opioid binding: QSAR analysisof tyrosine replacement in a nonselective deltorphin analog", Deborah L. Heyl, Stephen E. Schullery, Kutralanathan Renganathan, Malika N. Jayamaha, David W. Rodgers, and John R. Traynor (2003) Bioorganic & Medicinal Chemistry, 11/17, 3761-3768.

"The role of backbone conformation in deltorphin II binding: A QSAR study of new analogs modified in the 5, 6 positions of the address domain", Stephen E. Schullery, David W. Rodgers, Sakambari Tripathy, Don Eranda Jayamaha, Medha D. Sanvordekar, Kutralanathan Renganathan, Carol Mousigian, and Deborah L. Heyl (2001) Bioorganic & Medicinal Chemistry 9/10, 2633-2642.

"The role of backbone conformation in deltorphin II binding: A QSAR study of new analogs modified in the 5, 6 positions of the address domain", Stephen E. Schullery, David W. Rodgers, Sakambar Tripathy, Don Eranda Jayamaha, Medha D. Sanvordekar, Kutralanathan Renganathan, carol Mousigian and Deborah L. Heyl (2000) Bioorganic & Medicinal Chemistry 9/10, 2633-2642.

"Synthesis of a New Group of Deltorphin I/II Alalogs Modified in the Address Domain with gamma-Amino Acids, and QSAR Study of their delta/mu Opioid Binding", Debroah L. Heyl, Medha D. Sanvordekar, Guzin Dogruyol, Mohamed D. Salamoun, David W. Rodgers, Kutralanathan Renganathan, Carol Mousigian, Stephen E. Schullery (1999) Protein and Peptide Letters, 6(6), 359-366

"Binding to d and m opioid receptors by deltorphin I/II analogs modified at the Phe3 and Asp4/Glu4 side chains: A report of 32 new analogs and a QSAR study", Stephen E. Schullery, Tasneem Mohammedshah, Hafida Makhlouf, Eleanor L. Marks, Benjamin S. Wilenkin, Sharleen Escobar, Carol Mousigian, and Deborah L. Heyl (1997) Bioorganic and Medicinal Chemistry, 5(12), 2221-2234.

"Structural requirements for binding to the delta opioid receptor: Alkyl replacements at the third residue of deltorphin I", Deborah L. Heyl, Hassiba Bouzit, and Carol Mousigian (1996) Letters in Peptide Science, 2, 277-284.

"Opioid receptor binding requirements for the delta-selective peptide deltorphin I: Phe3 replacement with ring-substituted and heterocyclic amino acids", Deborah L. Heyl, Meena Dandabathula, Kathleen R. Kurtz, and Carol Mousigian (1995) Journal of Medicinal Chemistry, 38, 1242-1246.

"Substitution of aromatic and nonaromatic amino acids for the Phe3 residue in the delta-selective opioid peptide deltorphin I: Effects on binding affinity and selectivity", Deborah L. Heyl, Sharon J. Schmitter, Hassiba Bouzit, Thomas W. Johnson, Angela M. Hepp, Kathleen R. Kurtz, and Carol Mousigian (1994) International Journal of Peptide and Protein Research, 44, 233-238.

Invited Review: "Developments in the structure-activity relationships for the delta-selective opioid peptides of amphibian skin", D.L. Heyl and S.E. Schullery (1997) Current Medicinal Chemistry, 4, 117-150.

Honors and Awards

Ronald W. Collins Distinguished Faculty Award, Research II, 2009

Professional Affiliations

American Chemical Society
American Peptide Society

Courses Taught

Fundamentals of Chemistry Lab (Chem 118)
Fundamentals of Organic and Biochemistry (Chem 120)
Survey of Organic Chemistry (Chem 270-271)
Foundations of Biochemistry (Chem 351)
Biochemistry I and II (Chem 451-453)
Medicinal Chemistry and Drug Design (Chem 557)
Biochemistry III (Chem 551)
Special Topics in Biochemistry (Chem 591)

The Department of Chemistry is part of the College of Arts & Sciences, 214 Pray-Harrold