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Thesis
Inhibition of HIV-1 Matrix Functions by Novel Inhibitor, MTI-14
Master of Science (M.S.), Drexel University
May 2018
DOI:
https://doi.org/10.17918/D8RQ3M
Abstract
Human Immunodeficiency Virus type 1 (HIV-1), the causative agent of Acquired Immunodeficiency Syndrome (AIDS), affects the lives of millions of people worldwide. Currently combination therapies represent the best treatment for patients by employing multiple HIV-1 inhibitors to combat infection and viral replication. Combination therapies have been successful in lowering patient blood viral levels and increased life expectancy. Unfortunately, multi-drug resistance and severe cumulative drug toxicities involved with these treatments remain a limiting factor of treatment. The matrix protein of HIV-1 represents an attractive drug target for small molecule inhibitors of viral replication. The late stage replication functions of matrix are vital for the production of infectious and replication effective virus. Matrix is the N-terminal component of the Pr55 Gag polyprotein, found predominantly in the late stages of viral replication. Structural studies of matrix show that it can form a trimer or a hexamer of trimers as well as existing as a monomer following maturation. A few groups, including our own, have begun to develop small molecule inhibitors directed against matrix. One of the first compounds discovered to bind to matrix was compound 9, created by a team at Boehringer Ingelheim Ltd. However, compound 9 suffers from poor aqueous solubility and permeability as well as other metabolic issues, preventing it from being a viable lead compound. Using in silico prediction of ADME properties, high-content pharmacophore based bioisosteric replacement, rational drug design and chemical synthesis, we have discovered a novel series of HIV-1 inhibitors. Based on antiviral studies and NMR chemical shift analysis, MTI-14 was chosen for mechanism of action studies. MTI-14 can bind directly to matrix and inhibit its late stage functions. Mutational analysis of matrix has demonstrated that changes in amino acid residues localized near the PI(4,5)P2 binding site confer resistance to MTI-14 inhibition. Exciting preliminary evidence suggests that MTI-14 treatment can result in an envelope dependent decrease in infectivity. MTI-14 represents the first step in creating new reagents with which to study matrix functions. It is our hope that with the discovery of this first in class matrix inhibitor, MTI-14, further optimization will lead to a clinical therapeutic to combat HIV-1 infection.
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Details
- Title
- Inhibition of HIV-1 Matrix Functions by Novel Inhibitor, MTI-14
- Creators
- Andrea Rosenkranz - DU
- Contributors
- Todd Strochlic (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- vii, 68 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 8129; 991014632535604721