Development of Potent and Highly Selective Epoxyketone-based Plasmodium Proteasome Inhibitors
Creators
- 1. University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, Scripps Institution of Oceanography, UNITED STATES.
- 2. Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences: Ustav organicke chemie a biochemie Akademie ved Ceske republiky, Organic Chemistry and Biochemistry, CZECH REPUBLIC, University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, UNITED STATES.
- 3. University of California San Diego, Medicine, UNITED STATES.
- 4. University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, UNITED STATES
- 5. University of California San Diego, Scripps Institution of Oceanography, UNITED STATES
- 6. Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences: Ustav organicke chemie a biochemie Akademie ved Ceske republiky, Organic Chemistry and Biochemistry, CZECH REPUBLIC
- 7. University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, UNITED STATES.
Description
Here we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in vitro potency for blood-stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,000-fold greater selectivity for erythrocytic-stage P. falciparum over HepG2 and H460 cells, which is largely driven by the accommodation of the parasite proteasome for a D-amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. We isolated the proteasome from P. falciparum cell extracts and determined that the best compound is 171-fold more potent at inhibiting the β5 subunit of P. falciparum proteasome when compared to the same subunit of the human constitutive proteasome. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti-malarial drugs.
Files
Chemistry A European J - 2023 - Almaliti - Development of Potent and Highly Selective Epoxyketone‐based Plasmodium.pdf
Files
(1.9 MB)
Name | Size | Download all |
---|---|---|
md5:00638b56ce32d5dec64a90302b495961
|
1.9 MB | Preview Download |