Structure-Based Design and Synthesis of Novel Inhibitors of HIV-1 Protease and Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1

Heather L Osswald, Purdue University


HIV-1 protease is a critical enzyme in the life cycle of the human immunodeficiency virus (HIV). Targeting this enzyme halts the processing of viral polyproteins into mature and active enzymes which make virulent virions to further spread the infection. The development of the first HIV-1 protease inhibitor (PI) marked the beginning of highly active antiretroviral therapy (HAART) in 1995. Since then, many other first- and second-generation PIs have been designed and clinically evaluated. Still, mutations of the viral enzyme have resulted in drug-resistant strains of HIV, making the development of new, highly potent PIs of dire importance. To this end, a novel synthesis of bis-THF, an important structural feature of many PIs, has been designed. This new synthesis allows for both isomers of the bis-THF ligand to be synthesized without a chiral resolution step and with a handle for further derivatization at the C4 position, if desired. Also, a novel class of highly potent PIs is described. This class of inhibitors features modulation of interactions in the S1 hydrophobic pocket via the incorporation of an adamantyl moiety. This structural feature has never before been utilized in peptidomimetic inhibitors and resulted in very potent inhibitors with activity profiles similar to those of FDA approved therapies. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a highly sought-after target in Alzheimer’s disease drug development. This enzyme is responsible for the formation of amyloid beta (Aβ), the peptide which makes up the hallmark plaques found in the brains of Alzheimer’s patients. There have been great efforts from academic and industrial laboratories to develop a clinically viable BACE1 inhibitor. While many have been to clinical trials, none have been FDA approved. There has been some interest in curcumin, the colored component of turmeric, as a potential BACE1 inhibitor. A novel class of compounds based on this insight was designed. Work towards the synthesis and biological evaluation of these compounds has begun. Further work in the investigation of curcumin and its peptidomimetic derivatives is ongoing.




Ghosh, Purdue University.

Subject Area

Organic chemistry

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