Evidence of pyrimethamine and cycloguanil analogues as dual inhibitors of Trypanosoma brucei pteridine reductase and dihydrofolate reductase

DOI: 10.3390/ph14070636

Authors: Giusy Tassone (University of Siena) , Giacomo Landi (University of Siena) , Pasquale Linciano (University of Modena and Reggio) , Valeria Francesconi (University of Genoa) , Michele Tonelli (University of Genoa) , Lorenzo Tagliazucchi (University of Modena and Reggio Emilia) , Maria Paola Costi (University of Modena and Reggio Emilia) , Stefano Mangani (University of Siena) , Cecilia Pozzi (University of Siena)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Pharmaceuticals , VOL 14

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 11690

Abstract: Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine–nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy.

Journal Keywords: pyrimethamine; cycloguanil; derivatives; Trypanosoma brucei; pteridine reductase; dihydrofolate reductase; antifolate drug; dual inhibitor; X-ray crystallography; structure–activity relationship

Diamond Keywords: Sleeping Sickness; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 05/07/2021 13:13

Documents:
pharmaceuticals-14-00636-v2.pdf

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Catalysis Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)