A Synthetic Strategy for Conjugation of Paromomycin to Cell-Penetrating Tat(48-60) for Delivery and Visualization into Leishmania Parasites.

David Andreu,María A Abengózar,Luis Rivas,Maria Gallo,Sira Defaus

doi:10.1155/2017/4213037

Abstract

A successful approach to deliver paromomycin, a poorly absorbed aminoglycoside antibiotic, to parasite cells is reported, based on selective protection of amino and hydroxyl groups followed by conjugation to a fluorolabeled, PEG-functionalized cell-penetrating Tat(48-60) peptide. The resulting construct is efficiently internalized into Leishmania cells, evidencing the fitness of cell-penetrating peptides as vectors for efficiently transporting low-bioavailability drugs into cells.

Highlights

Aminoglycosides are broad spectrum antibiotics used as alternative antiparasitic agents that induce a deleterious effect on proliferation by interfering with the parasite’s protein synthesis machinery [1, 2]
Recent reports on PMM selective antiparasitic effect on Leishmania ribosomes [6] and its low toxicity to mammalian cells have placed it on the list of essential medicines needed in a basic health system [7]
In an attempt to further expand this proof-of-principle, we report the synthesis of a PMM-Cell-penetrating peptides (CPPs) platform that integrates a PEG-like spacer and a fluorescent tag for imaging purposes

Summary

Introduction

Aminoglycosides are broad spectrum antibiotics used as alternative antiparasitic agents that induce a deleterious effect on proliferation by interfering with the parasite’s protein synthesis machinery [1, 2]. Recent reports on PMM selective antiparasitic effect on Leishmania ribosomes [6] and its low toxicity to mammalian cells have placed it on the list of essential medicines needed in a basic health system [7]. Miltefosine (hexadecylphosphocholine), a drug to which Leishmania is resistant due to poor accumulation, can be conjugated to a reference CPP such as Tat(48-60) to give a formulation with high absorption and parasiticidal activity that effectively defeats this resistance and expands the spectrum of susceptible trypanosomatids [16]. Our results open the way to antiparasitic drugs with improved pharmacokinetic properties (Figure 1)

Methods

Results

Conclusion