Peptide Dimerization as a Strategy for the Development of Antileishmanial Compounds

Area of Science:

• Parasitology
• Medicinal Chemistry
• Drug Discovery

Background:

• Leishmaniasis is a significant global public health issue, particularly in Brazil.
• Current treatments for leishmaniasis face challenges including limited drug availability, side effects, and emerging drug resistance.
• There is a critical need for novel therapeutic agents to combat leishmaniasis.

Purpose of the Study:

• To identify novel leishmanicidal compounds using a peptide dimerization strategy.
• To investigate the mechanism of action of these identified compounds.
• To evaluate the potency and selectivity of dimeric peptides against Leishmania species.

Main Methods:

• Peptide dimerization strategy was employed to create novel compounds.
• Compounds were evaluated for leishmanicidal activity against *Leishmania mexicana* and *Leishmania amazonensis*.
• Mechanism of action was explored through inhibition assays targeting parasite cysteine protease and membrane interaction studies using flow cytometry, permeabilization, and fluorescence microscopy.

Main Results:

• The dimeric peptide (TSHa)₂K demonstrated significantly higher potency and selectivity compared to its monomeric form.
• The identified compounds effectively inhibited the parasite cysteine protease, a key target for leishmaniasis treatment.
• Selective interaction with parasite membranes was confirmed through various biophysical assays.

Conclusions:

• Dimerization of the TSHa peptide yields potent and selective leishmanicidal compounds.
• These compounds represent promising candidates for further development as anti-leishmaniasis therapeutics.
• The identified molecules warrant progression into in vivo studies using animal models for leishmaniasis treatment.