Greater than 1.4 billion people in the world are affected by Neglected Tropical Diseases (NTDs). The effectiveness of treatment of NTDs has been diminished due to the following problems: 1) resistance spreads and develops quickly, 2) the parasites do not actively transport drugs into their bodies, 3) many drugs are only effective during specific developmental stages of the parasites, and 4) the drugs tend to target only a specific type of parasite. It is now known that free-living and parasitic nematodes are unable to synthesize heme, and without it they are unable to survive and reproduce. Leishmania are heme auxotrophs that lack the necessary genes to biosynthesize heme, which plays an essential role in the replication and survival of the parasite. LHR-1 is a small 20 kDa protein, with four predicted transmembrane domains, that localizes to acidic intracellular compartments and the plasma membrane of promastigotes and amastigote stages of the parasite. It functions in the direct transport of heme from the environment into the cytoplasm and is essential for virulence. Importantly, LHR1 transcript levels increase when the parasites are grown under heme depleted conditions, is involved in the control of intracellular heme pools (in host macrophage), can rescue the growth of a yeast strain defective in heme biosynthesis, and can directly transport radioactive heme when expressed in a yeast system. Loss of a single LHR-1 allele results in severe growth defects, whereas a null mutant is not viable. These results along with the low sequence homology to the human homolog (hHRG-1) make LHR-1 an attractive drug target. Several antagonists were identified from an initial high throughput screen that specifically inhibit the heme transport function of the Leishmania LHR1 but not the corresponding human homolog (hHRG1). Herein we detail the design, synthetic strategy, and structure-activity relationships of novel low-µM selective inhibitors of LHR-1.

Inhibitors of LHR-1 as novel anti-parasitic drugs

252nd National Meeting (2016)

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