<p>Since 1981, HIV/AIDS has affected over 70 million
individuals worldwide. Due to the
incorporation of Combination Antiretroviral Therapy (cART), this deadly virus
has now become a manageable chronic illness with a reduction in mortality and
morbidity rates. Combination therapy
targets multiple stages of the HIV replication cycle including fusion, entry,
reverse transcription, integration, and maturation. The HIV-1 protease enzyme is responsible for cleavage
and processing of viral polyproteins into mature enzymes and is a common
therapeutic target for inhibition of HIV.
To date, there have been many protease inhibitors approved by the FDA
and introduced into the market. However,
mutations within the protease enzyme has rendered some of these inhibitors ineffective. This has led to an ever-growing need to
develop novel protease inhibitors to combat drug resistance through
mutations. Described herein is the
design, synthesis, and biological evaluation of HIV-1 protease inhibitors
featuring a novel hexahydropyrrolofuran (HPF) bicyclic scaffold as a P<sub>2</sub>
ligand to target binding interactions with Asp29 and Asp30. The HPF ligand provides a molecular handle
that allows for further structure-activity discoveries within the enzyme. The HIV-1 protease inhibitors discussed
feature carbamate, carboxamide, and sulfonamide derivatives which displayed good
to excellent activity.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12218546 |
| Date | 30 April 2020 |
| Creators | Joseph D Bungard (8782670) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/Design_and_Synthesis_of_HIV-1_Protease_Inhibitors_Featuring_a_Bicyclic_Hexahydropyrrolofuran_Scaffold/12218546 |
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