Novel and Selective Rhipicephalus microplus Triosephosphate Isomerase Inhibitors with Acaricidal Activity.

Luiz Saramago,Beatriz Aguirre-López,Mauricio Cabrera,Ruy Pérez-Montfort,Hugo Cerecetto,Alicia Merlino,Jorge Moraes,Itabajara Da Silva Vaz Junior,Mercedes González,Maria Alzugaray,Guzmán Álvarez,Helga Gomes,Elena Aguilera,Rodrigo Nunes Da Fonseca,Nallely Cabrera

doi:10.3390/vetsci5030074

Abstract

The cattle tick Rhipicephalus microplus is one of the most important ectoparasites causing significant economic losses for the cattle industry. The major tool of control is reducing the number of ticks, applying acaricides in cattle. However, overuse has led to selection of resistant populations of R. microplus to most of these products, some even to more than one active principle. Thus, exploration for new molecules with acaricidal activity in R. microplus has become necessary. Triosephosphate isomerase (TIM) is an essential enzyme in R. microplus metabolism and could be an interesting target for the development of new methods for tick control. In this work, we screened 227 compounds, from our in-house chemo-library, against TIM from R. microplus. Four compounds (50, 98, 14, and 161) selectively inhibited this enzyme with IC50 values between 25 and 50 μM. They were also able to diminish cellular viability of BME26 embryonic cells by more than 50% at 50 μM. A molecular docking study showed that the compounds bind in different regions of the protein; compound 14 interacts with the dimer interface. Furthermore, compound 14 affected the survival of partially engorged females, fed artificially, using the capillary technique. This molecule is simple, easy to produce, and important biological data—including toxicological information—are available for it. Our results imply a promising role for compound 14 as a prototype for development of a new acaricidal involving selective TIM inhibition.

Highlights

The cattle tick Rhipicephalus microplus is the most significant ectoparasite in tropical and sub-tropical regions, with associated economic losses estimated at US $22–30 billion annually [1].Its bite causes damage to the skin, promoting local inflammation that harms the animal leather industry
There are five cysteine residues that occur in almost all Triosephosphate isomerase (TIM) from ticks, but are not present in B. taurus TIM (Figure S1 in supporting information)
A phylogenetic analysis of TIMs from ticks was constructed based on their amino acid sequences (Figure 1)

Summary

Introduction

The cattle tick Rhipicephalus microplus is the most significant ectoparasite in tropical and sub-tropical regions, with associated economic losses estimated at US $22–30 billion annually [1]. Its bite causes damage to the skin, promoting local inflammation that harms the animal leather industry. It affects animal weight gain and, milk and meat production [2]. It is the most important vector for cattle disease agents, such as Babesia spp. and Anaplasma spp. The continuous and indiscriminate use of acaricides has led to chemico-resistant ticks [5,6]

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Discussion

Conclusion