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

Figures & data

Figure 1 General framework for the discovery and validation of novel compounds for the treatment of Chagas disease.

Abbreviations: CYP51, 14-α demethylase; DMPK, Drug Metabolism and Pharmacokinetics; gLogD, Distribution coefficient; hCYP3A4, Human cytochrome P450 3A4; hERG, Human ether a-go-go gene; HTS, High throughput screening; IC₅₀, Half maximal inhibitory concentration; PK/PD, Pharmacokinetics and pharmacodynamics; SI, Selectivity Index; MA, Maximal inhibitory activity, Sol, Solubility at physiological pH.

Table 1 Commonly Used Criteria to Determine the Progression of a Compound in Phenotypic Development Pathways

	Chatelain, Ioset 2017^Citation61	Martin-Escolano, 2020^Citation23	Kratz et al, 2022^Citation72	Neitz 2015^Citation73	Germain 2011^Citation40
IC50	< 5 μM	< 5 μM	< 5 μM ideally < 1 uM)	< 1 μM	<1 μM
Max. activity	> 90%	> 90%	> 95%	-	>55%
SI	> 10 (3T3 cells)	> 10 (ideally >100)	> 10 (> 50)	>25	>100
MoA	Fast-acting	Fast-acting, cidal	Fast-acting, cidal	-	-
TcCYP51 activity	> 10 μM	-	Removal of CYP51 inhibitors	>5 μM	-
Solubility	> 50 μg/mL			>50 μM^a	>100 μM
CYP 3A4	> 10 μM			>25μM	-
Suggested parasite genotypes to be targeted	All (priority to TcI, TcII, TcV, TcVI)	All	Stable activity among strains	Stable activity among strains (evaluated in TcI, TcII, and TcVI)	Only evaluated in DTU VI

Notes: Data from Chatelain, Ioset 2017,⁶¹ Martín-Escolano, 2020,²³ Kratz et al 2022,⁷² Neitz 2015,⁷³ and Germain 2011.⁴⁰ aSaturation in aqueous solution at pH 6.8.

Abbreviations: IC₅₀: Half maximal inhibitory concentration, MoA: Mechanism of action, SI: Selectivity Index, CYP51: 14-α demethylase.

Table 2 Compounds Under Evaluation for Their Use in Chagas Disease

Compound	Class	Stage of Development	Comments
Fexinidazole	Nitroimidazole	Phase II clinical trial	Significant haematological and neuropsychiatric alterations following standard treatment regimes. Lack of anti-parasitic efficacy in short-term regimes.^Citation161
LXE408	Proteasome inhibitor	Phase I clinical trial^a	Derived from compound GNF6702, which demonstrated activity against different Leishmania species and T. cruzi^Citation44,Citation162
AN15368	Oxaborole	Pre-clinical evaluation	Remarkable in vitro and in vivo anti-parasitic activity, including in naturally infected NHPs.^Citation82
DNDi-6148	Oxaborole	Phase I clinical trial^a	Demonstrated anti-kinetoplastid activity in vivo. Safe in phase I trial.^Citation163

Notes: ^aCurrently evaluated for use in leishmaniasis but suggested as candidate drugs for treatment of Chagas disease.

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