Chemistry & Biochemistry (Mohammad Halim)
Developing Peptide Drugs for Alzheimer and Covid-19 Diseases
First-Year Scholars: Nataly Barahona, Vincent Dupard, Kira Galloway, Ishani Ganorkar, Cecilia Le, Maryam
Najeeb, Shubh Patel, Lillian Schwartz, Khang Tran, & Matias Van Huffel
-
Peptide therapeutics are very attractive over small-molecule medications, as they
are highly selective, well-tolerated, and have less adverse effects. Generally, the
poor oral bioavailability of peptides requires subcutaneous administration. A short
half-life poses additional challenges for their formulation and clinical utility.
Despite these obstacles, the current rate of approval by the FDA for peptide drugs
is twice as fast as for small molecules. Worldwide, 88 peptide drugs are approved,
and 170 peptides are currently being evaluated in clinical trials. Peptide stapling,
a cyclization technique, is a widely used approach to develop staple peptides. However,
the traditional hydrocarbon and triazole/disulfide stapling methods produced low yield
and required catalyst separation. Hence, a novel high yielding stapling method is
required.
Our long-term goal is to design, synthesize and evaluate the efficacy of novel pi-pi
staple and potentially orally active peptide targeting the various proteins related
to Alzheimer and Covid-19 diseases. This project has following two specific aims:
Aim 1. To develop potent staple peptide mimetics: A pool of novel pi-pi staple analogues will be designed and optimized targeting Acetylcholinesterase (AChE) and main protease (3CLpro of SARS-CoV-2) which are major drug targets in Alzheimer’s and Covid-19, respectively. Computer aided design and solid phase peptide synthesis protocol will be employed. Secondary structure of these peptides will be elucidated by circular dichroism (CD) and NMR spectroscopy. Structural insights of the peptide binding and interaction with viral proteins will be investigated by hydrogen deuterium exchange mass spectrometry (HDX-MS).
Aim 2. To evaluate toxicity, inhibition efficiency, metabolism and stability. Only
peptides with no/minimal toxicity will be considered. To assess the inhibition efficiency,
various assays will be conducted. In-vitro metabolic and stability assays will be
performed. The best analogues will be improved by installing fatty-acid tag, sugar-complex,
and cyclodextrin improving half-life, and oral bioavailability.
The expected outcome of this project is to develop peptide-based drugs to treat dementia
and infectious diseases and advance our knowledge of how these peptides can be further
improved.
|
-
This research training will help students to learn basic biochemistry, peptide synthesis, molecular modeling, mass spectrometry-based assay and gain experiences on performing interdisciplinary research, collecting, and analyzing experimental and computational data, interpreting, and presenting results, presenting in conference, writing, and publishing manuscripts. These diverse research experiences in peptide synthesis, molecular modeling and peptide characterization by liquid chromatography and mass spectrometry, and biological assays will help students to pursue their PhD on biomedical science, obtain their degree in MD/PhD or secure position in CDC, FDA, and pharmaceutical/biochemical industry |
-
Student will do various tasks in the different phase of the projects including:
i) assignments ii) reading and reviewing scientific articles iii) performing computer aided peptide design iv) synthesizing and characterizing peptides v) acquiring and interpreting mass spectrometry-based inhibition and metabolic assays vi) drafting poster, presentation, and manuscript.
|
-
Modality (Face-to-Face, Hybrid, Online)
-
|