# Target-specific antimalarial compound identification using phenotypic assays

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $376,500

## Abstract

Our ability to effectively treat malaria is threatened by increasingly widespread resistance to the limited number
of frontline antimalarial drugs available. Therefore, new strategies for identifying novel chemical probes and/or
therapeutic leads centered around biologically validated targets are critically needed. Here, we propose the
integrated use of functional genetics and chemical biology approaches to enable more effective target-driven
antimalarial drug discovery. The long-term goal is to take advantage of recent advances in malaria parasite
genetics to qualify and prioritize previously unexplored biological targets and/or pathways for therapeutics
discovery efforts. By focusing on this target category, we envision achieving the capability to discover chemical
probes that better allow us to define fundamental biology and elucidate new options for antimalarial therapy,
and ultimately identify effective therapeutic strategies against multidrug resistant parasites that are becoming
increasingly prevalent and widespread. While target-based drug discovery is conceptually appealing, it has not
been as successful as phenotypic screens in identifying approved antimalarial agents. However, given the
substantial amount of genomics data and the improved functional genetics tools now available, more effective
approaches for target-based discovery could dramatically improve this. The objectives of this research are to
(1) establish an innovative approach for improving target-specific drug discovery while (2) seeking to determine
potential probe/drug-like molecules that are selective against several prioritized target candidates. While it
relatively is straightforward to discover small molecules with in vitro activity against a target, prioritizing
compounds that truly act via that target to dictate the biological outcome has been challenging. Conversely,
phenotypic screens immediately establish the biological efficacy of a given compound. However, identifying the
target(s) through which these compounds act biologically is time consuming and often unsuccessful. In both
cases, the ability to synergistically leverage empirical and rational (e.g. structure-based) approaches for lead
compound optimization is adversely impacted. In this proposal, we integrate use of state-of-the-art functional
genetic tools to encode target-specific information into phenotypic screens to facilitate rapid identification of
compounds interacting with pre-specified targets. We seek to establish a generalized framework applicable to
a broad range of targets varying in their proposed biological function, subcellular localization, biochemical and
biophysical properties. We envision developing standardized assays and analytical pipelines to facilitate
evaluation of various compound collections. The current proposal will focus on developing and validating low-
to-moderate throughput assays. The proposed research is significant because it simultaneously leverages
key strengths of usi...

## Key facts

- **NIH application ID:** 10177856
- **Project number:** 5R01AI141543-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** JACQUIN C NILES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,500
- **Award type:** 5
- **Project period:** 2019-06-03 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177856

## Citation

> US National Institutes of Health, RePORTER application 10177856, Target-specific antimalarial compound identification using phenotypic assays (5R01AI141543-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10177856. Licensed CC0.

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