Structural basis for selective targeting of leishmanial ribosomes: Aminoglycoside derivatives as promising therapeutics

Shalev, Moran; Rozenberg, Haim; Smolkin, Boris; Nasereddin, Abedelmajeed; Kopelyanskiy, Dmitry; Belakhov, Valery; Schrepfer, Thomas; Schacht, Jochen; Jaffe, Charles L.; Adir, Noam; Baasov, Timor

doi:10.1093/nar/gkv821

Title: Structural basis for selective targeting of leishmanial ribosomes: Aminoglycoside derivatives as promising therapeutics

Journal Article · Tue Aug 11 00:00:00 EDT 2015 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkv821· OSTI ID:1223387

Shalev, Moran ^[1]; Rozenberg, Haim ^[2]; Smolkin, Boris ^[3]; Nasereddin, Abedelmajeed ^[4]; Kopelyanskiy, Dmitry ^[4]; Belakhov, Valery ^[3]; Schrepfer, Thomas ^[5]; Schacht, Jochen ^[5]; Jaffe, Charles L. ^[4]; Adir, Noam ^[3]; Baasov, Timor ^[3]

Israel Institute of Technology, Haifa (Israel); Weizmann Institute of Science, Rehovot (Israel)
Weizmann Institute of Science, Rehovot (Israel)
Israel Institute of Technology, Haifa (Israel)
Hebrew Univ.-Hadassah Medical School, Jerusalem (Israel)
Univ. of Michigan Medical School, Ann Arbor, MI (United States)

Leishmaniasis comprises an array of diseases caused by pathogenic species of Leishmania, resulting in a spectrum of mild to life-threatening pathologies. Currently available therapies for leishmaniasis include a limited selection of drugs. This coupled with the rather fast emergence of parasite resistance, presents a dire public health concern. Paromomycin (PAR), a broad-spectrum aminoglycoside antibiotic, has been shown in recent years to be highly efficient in treating visceral leishmaniasis (VL)—the life-threatening form of the disease. While much focus has been given to exploration of PAR activities in bacteria, its mechanism of action in Leishmania has received relatively little scrutiny and has yet to be fully deciphered. In the present study we present an X-ray structure of PAR bound to rRNA model mimicking its leishmanial binding target, the ribosomal A-site. We evaluate PAR inhibitory actions on leishmanial growth and ribosome function, as well as effects on auditory sensory cells, by comparing several structurally related natural and synthetic aminoglycoside derivatives. The results provide insights into the structural elements important for aminoglycoside inhibitory activities and selectivity for leishmanial cytosolic ribosomes, highlighting a novel synthetic derivative, compound 3, as a prospective therapeutic candidate for the treatment of VL.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1223387

Journal Information:: Nucleic Acids Research, Vol. 43, Issue 17; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 22 works

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