Discovery of Boronic Esters as Building Blocks for Potential Aspartic Protease Enzyme Inhibitors ‡ Callan McLoudrey, Emmerson Miller † , Jackson Tieber, Charlie Ericksson, Alexi Granados-Ramos † , Chase Perez, Megan Quinn, Quaid Hunt, Kayden Stiner, Brett Vagt, Michael Frank Project Mentor(s): Levente Fabry-Asztalos, PhD In 2024, over 30 million people underwent antiretroviral therapy to treat their HIV infection. Modern treatments have proven to be effective; however, the increase in drug-resistant variants, low bioavailability, toxicity, and adverse side effects requires the continued investigation of potential building blocks for future drug development. In human and viral development, aspartic proteases are critical in processing proteins. Within viral systems, like HIV, this enzyme aids in forming mature virions capable of infecting new cells to initiate their replication cycle, making this a prime target for novel antiviral therapies. Boron-containing compounds have shown promise in reducing HIV-1 activity by binding to the active site of the protease enzyme. The unique coordinative system in boron- containing compounds allows them to act as dual-mode inhibitors, preventing substrate binding through competitive inhibition, reducing the dimerization of its monomers, and halting the replication cycle. These boronic esters will be synthesized by using benzylboronic acid pinacol ester undergoing a Matteson homologation reaction, then a nucleophilic substitution will take place with various R-groups. The goal of this research is to synthesize a library of novel boronic esters and improve current methods to establish lead compounds for aspartic protease enzyme inhibitors. Presentation Type: Poster Presentation (May 21, 9:30am–3:00pm) Keywords : Medicinal Chemistry, Inhibitors, HIV-1, Organic Chemistry, Viruses SOURCE Form ID: 153 Synthesis of ⍺ -Aminoboronic Acids and their Analogues: Building Blocks for Potential Enzyme Inhibitors ‡ Emmerson Miller † , Alexi Granados-Ramos † , Hannah Huber, Andrew S. Wilson Project Mentor(s): Levente Fabry-Asztalos, PhD Viral infectious diseases and drug-resistant bacteria continue to impose a significant challenge on global health. Although current antiviral drugs are available, they meet constraints due to low bioavailability, toxicity, adverse drug effects, and drug-resistance. With pathogenetic viruses being capable of forming mutations to current treatments, novel options are vital for the future of medicinal care. In the last few decades, ⍺ -aminoboronic acids have served as important building blocks for biomedical applications, particularly as proteasome and potential aspartic protease inhibitors. Boron contains a dynamic coordinate system, which allows for more effective binding to target active sites when compared to their carbon analogues. Boron-containing compounds have shown promise as both competitive and associative enzyme inhibitors, further supporting our goal of synthesizing novel ⍺ -aminoboronic acids. This research aims to expand the library of ⍺ -aminoboronic acids and their analogues to develop a larger variety of novel compounds that target aspartic protease enzymes of pathogenic viruses involved in disease states such as HIV and malaria. The reactions enable precise incorporation of boron atoms into the molecular framework to optimize enzyme-target binding and chemical stability. Reactions performed include esterification of alkylboronic acids, catalyzed homologation, dehalogenation of ⍺ -haloboronic esters using nucleophilic substitution with hexamethyldisilazane, and desilylation via acidification. We hope these novel compounds will potentially serve as building blocks for peptide-based inhibitors, with the potential for higher binding affinity, better bioavailability profiles, lower toxicity, and fewer side effects. Presentation Type: Poster Presentation (May 21, 9:30am–3:00pm) Keywords : Medicinal chemistry, Enzymes, HIV-1, Organic chemistry, Viruses SOURCE Form ID: 197
110
Made with FlippingBook interactive PDF creator