Developing a 3D Physical Model of HIV Protease to Explore Drug Resistance to Tipranavir and Darunavir

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HIV infections affect over 38 million people worldwide and cause approximately one million deaths every year. Despite advances in antiretroviral therapies and disease prevention strategies, drug resistance remains a major challenge in HIV treatment. HIV protease plays a key role in viral replication by facilitating the peptide bond hydrolysis reactions necessary for the development of functional viral particles. Diverse inhibitors have been developed to target the active site and substrate envelope of HIV protease. While these drugs have been effective at inactivating the enzyme, mutations at the active site give rise to HIV resistance strains which are insensitive to protease inhibitors. The goal of this project was to create 3D printed models of HIV protease to illustrate the mechanisms of action of two inhibitors, Tipranavir and Darunavir, and the mutations involved in the development of resistance to these drugs. Database searches and sequence alignments were performed to identify conserved amino acids and structural features important in the catalytic mechanism of HIV proteases. Details of the protein structure and its interaction with Tipranavir and Darunavir were obtained by analyzing the Protein Databank Files: 6DIF, 6DGX, 6OPS, and 6DH6. To construct the physical models, the structure files were imported into Jmol and modified into a format suitable for 3D printing using scripts created by undergraduate researchers. The 3D models feature the overall structure of HIV protease, and its inhibitor molecules, Tipranavir and Darunavir. An active site box was constructed to illustrate the biochemical interactions between the enzyme and the inhibitors. The physical models also highlight key amino acids such as Asp25, Ile50, Val82, and Val84, which are critical for catalytic activity and the development of drug resistance. Magnetic pieces were created to show the effects of mutations in inhibitor binding and enzyme activity. A Jmol tutorial was designed to complement the 3D models and assess students’ learning of the structure and function of HIV protease.Support or Funding InformationThis project is funded in part by NSF‐IUSE #1725940 for the CREST Project.