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Development of subunit selective substrates for Trichomonas vaginalis proteasome

Authors :
Pavla Fajtova
Brianna M Hurysz
Yukiko Miyamoto
Mateus Serafim
Zhenze Jiang
Diego F. Trujillo
Lawrence Liu
Urvashi Somani
Jehad Almaliti
Samuel A. Myers
Conor R. Caffrey
William H. Gerwick
Christopher J Kirk
Evzen Boura
Lars Eckmann
Anthony J O’Donoghue
Source :
bioRxiv
Publication Year :
2023
Publisher :
Cold Spring Harbor Laboratory, 2023.

Abstract

The protozoan parasite,Trichomonas vaginalis(Tv) causes trichomoniasis, the most common, non-viral, sexually transmitted infection in the world. Only two closely related drugs are approved for its treatment. The accelerating emergence of resistance to these drugs and lack of alternative treatment options poses an increasing threat to public health. There is an urgent need for novel effective anti-parasitic compounds. The proteasome is a critical enzyme forT. vaginalissurvival and was validated as a drug target to treat trichomoniasis. However, to develop potent inhibitors of theT. vaginalisproteasome, it is essential that we understand which subunits should be targeted. Previously, we identified two fluorogenic substrates that were cleaved byT. vaginalisproteasome, however after isolating the enzyme complex and performing an in-depth substrate specificity study, we have now designed three fluorogenic reporter substrates that are each specific for one catalytic subunit. We screened a library of peptide epoxyketone inhibitors against the live parasite and evaluated which subunits are targeted by the top hits. Together we show that targeting of the β5 subunit ofT. vaginalisis sufficient to kill the parasite, however, targeting of β5 plus either β1 or β2 results in improved potency.

Subjects

Subjects :
Article

Details

Language :
English
Database :
OpenAIRE
Journal :
bioRxiv
Accession number :
edsair.doi.dedup.....d83517afa78a9248add719062c31304c