Past and future of trypanosomatids high-throughput phenotypic screening

Abstract

Diseases caused by trypanosomatid parasites affect millions of people mainly living in developing countries. Novel drugs are highly needed since there are no vaccines and available treatment has several limitations, such as resistance, low efficacy, and high toxicity. The drug discovery process is often analogous to finding a needle in the haystack. In the last decades a so-called rational drug design paradigm, heavily dependent on computational approaches, has promised to deliver new drugs in a more cost-effective way. Paradoxically however, the mainstay of these computational methods is data-driven, meaning they need activity data for new compounds to be generated and available in databases. Therefore, high-throughput screening (HTS) of compounds still is a much-needed exercise in drug discovery to fuel other rational approaches. In trypanosomatids, due to the scarcity of validated molecular targets and biological complexity of these parasites, phenotypic screening has become an essential tool for the discovery of new bioactive compounds. In this article we discuss the perspectives of phenotypic HTS for trypanosomatid drug discovery with emphasis on the role of image-based, high-content methods. We also propose an ideal cascade of assays for the identification of new drug candidates for clinical development using leishmaniasis as an example.

State-of-the-Art in the Drug Discovery Pathway for Chagas Disease: A Framework for Drug Development and Target Validation

“… 51 Additionally, HCS is less likely to be negatively affected by interactions between compounds and reporter enzymes and substrates, or by the effect that colored compounds might have on spectrophotometric readings. 51 …”

“…38,39,50 Remarkably, beyond quantifying parasite growth, these assays can also provide data on the nature and timing of the observed anti-parasitic effects and on the effect of compounds on certain phenotypic characteristics of parasites and cells, including shape, size, presence of vacuoles, or organization of the kinetoplastid DNA (kDNA) and cytoskeleton. 51 Additionally, HCS is less likely to be negatively affected by interactions between compounds and reporter enzymes and substrates, or by the effect that colored compounds might have on spectrophotometric readings. Regardless of the method used to quantify anti-parasitic effects, it is essential to guarantee that these are specific and not derived from induced host cell damage or death.…”