Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens

Area of Science:

• Biochemistry
• Parasitology
• Drug Discovery

Background:

• Developing effective chemotherapy against eukaryotic pathogens like trypanosomes is difficult due to conserved drug targets and evolving resistance.
• Targeting macromolecular interactions, specifically transfer RNA (tRNA):aminoacyl-tRNA synthetase (aaRS) interactions, presents a novel therapeutic strategy.
• This approach hypothesizes that macromolecular interaction features diverge faster through coevolution, offering unique parasite-specific targets.

Purpose of the Study:

• To identify parasite-specific tRNA features conserved across trypanosome evolution.
• To validate tRNA:aaRS interactions as a druggable target for anti-trypanosomal therapies.
• To discover broad-spectrum anti-parasitic compounds targeting aaRS enzymes.

Main Methods:

• Computed tRNA Class-Informative Features for humans and eight trypanosome clades.
• Biochemically validated tRNA:aaRS interactions as drug targets.
• Screened a marine natural products library for inhibitors of Leishmania major and Trypanosoma cruzi aminoacyl-tRNA synthetases.

Main Results:

• Identified parasite-specific tRNA features conserved over 250 million years of trypanosome evolution.
• Discovered marine natural product fractions inhibiting Leishmania major alanyl-tRNA synthetase (AlaRS) without affecting the human homolog.
• Demonstrated cross-reactivity of these inhibitors against Trypanosoma cruzi AlaRS and identified inhibitors for Leishmania major threonyl-tRNA synthetase (ThrRS).

Conclusions:

• tRNA:aaRS interactions are a promising target for developing broad-spectrum anti-trypanosomal drugs.
• Marine natural products offer a source of novel inhibitors against key aaRS enzymes.
• Targeting multiple aaRS enzymes may reduce the likelihood of drug resistance evolution compared to single-target therapies.