Novel and Selective Rhipicephalus microplus Triosephosphate Isomerase Inhibitors with Acaricidal Activity

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.

Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity

“…Screening FhTIM. We hypothesized that a TIM dimer interface inactivator would be a successful strategy to identify molecules with selective antiparasitic activity [18][19][20] . Therefore, we selected 340 compounds from our in-house chemical collection and screened them against the isolated recombinant FhTIM.…”

Towards a Sustainable One Health Approach to Crimean–Congo Hemorrhagic Fever Prevention: Focus Areas and Gaps in Knowledge

“…Additionally, acaricidal compounds can have off-target effects, including toxicity to other organisms, and long-term environmental persistence [ 131 ]. For these reasons, the discovery and development of new synthetic acaricidal compounds has not been an actively pursued area of research in recent years [ 132 ].…”

“…Moreover, differences in cultivating and collecting plant materials (including variations in soil, climate, and other factors) for plant or extract production may affect downstream results [ 136 ]. Despite the limitations of current data, based on their historic use by rural livestock farmers, plant-based compounds may be a good future source of effective acaricidal preparations either as an extract or as a source of new synthetic acaricidal compounds [ 132 , 134 ].…”

Potential Site to Direct Selective Compounds in the Triosephosphate Isomerase for the Development of New Drugs

“…In the pharmaceutical industry, the development of selective drugs to an enzyme or the repositioning of commercial drugs, today, is booming. The glycolytic enzyme triosephosphate isomerase (TIM) has been used as a therapeutic target for the development of new drugs against various pathogenic organisms, such as, Trypanosoma cruzi, Trypanosoma brucei, Entamoeba histolytica, Giardia duodenalis, Trichomonas vaginalis , among others . Therefore, saving resources in the development of new drugs, by directing the interaction of pharmacological compounds to a specific interaction site with a high probability to be selective, represents an opportunity, for researchers who are looking for new molecules or pharmacological compounds that they do not have a reported use, or in the case, of wanting to find another use to conventional drugs, such as omeprazole against TIM [11] [12] .…”

“…In this study, we propose a potential site as a therapeutic target against the enzyme triosephosphate isomerase for drug development, and that this potential new drug could be safe to be used at humans. We determined the K in position 214 (near the sequence YGGSV−K214) is indispensable for the interaction with the tested compounds and it helps the interaction in the active site from TIM.…”