Discovery of P1-P2 depeptidized boronic acid based Plasmodium falciparum SUB1 inhibitor
- 1National Institute of Reseach and Innovation
Abstract
The Plasmodium falciparum subtilisin-like serine protease 1 (PfSUB1) is an essential enzyme required for parasite egress from host red blood cells and represents a promising target for antimalarial drugs. Peptidic boronic acids are potent reported PfSUB1 inhibitors, however their drug-likeness is limited by their pronounced peptidic character. Based on molecular docking studies using peptidic boronic acids, we designed a series of partially depeptidized PfSUB1 inhibitors by replacing the P1-P2 dipeptide fragment with a 3-aminomethylphenylboronic acid core. Structure-activity relationship (SAR) investigations targeting interaction with active-site residue Lys138 revealed that introducing a meta-carboxylate group (compound 3a) markedly enhanced inhibitory activity, yielding a low-nanomolar PfSUB1 inhibitor (IC50= 10.2 nM). Bioisosteric replacement of the carboxylic acid demonstrated that an N-acylsulfonamide group (compound 4k) retained high enzymatic potency (IC50= 13.5 nM)). In cellular assays against blood-stage P. falciparum (3D7 strain), the leading depeptidized boronic acids exhibited growth inhibition with values in the low-micromolar range suggesting that further structural modifications are needed to enhance membrane permeability across host and parasite membranes to reach exonemes prior to egress. Overall, this study validates the P1-P2 depeptidization of boronic acid scaffolds and provides key SAR insights for the rational design of non-peptidic PfSUB1-targeted antimalarials.
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BibTeX
@misc{kazia2026discovery,
title = {{Discovery of P1-P2 depeptidized boronic acid based Plasmodium falciparum SUB1 inhibitor}},
author = {A. Kazia and E. Lidumniece and C. Withers and O. Donnelly and D. A. Fidock and M. Blackman and A. Jirgensons},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.762536},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.762536v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Discovery of P1-P2 depeptidized boronic acid based Plasmodium falciparum SUB1 inhibitor
AU - A. Kazia
AU - E. Lidumniece
AU - C. Withers
AU - O. Donnelly
AU - D. A. Fidock
AU - M. Blackman
AU - A. Jirgensons
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.762536
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.762536v1
AB - The Plasmodium falciparum subtilisin-like serine protease 1 (PfSUB1) is an essential enzyme required for parasite egress from host red blood cells and represents a promising target for antimalarial drugs. Peptidic boronic acids are potent reported PfSUB1 inhibitors, however their drug-likeness is limited by their pronounced peptidic character. Based on molecular docking studies using peptidic boronic acids, we designed a series of partially depeptidized PfSUB1 inhibitors by replacing the P1-P2 dipeptide fragment with a 3-aminomethylphenylboronic acid core. Structure-activity relationship (SAR) investigations targeting interaction with active-site residue Lys138 revealed that introducing a meta-carboxylate group (compound 3a) markedly enhanced inhibitory activity, yielding a low-nanomolar PfSUB1 inhibitor (IC50= 10.2 nM). Bioisosteric replacement of the carboxylic acid demonstrated that an N-acylsulfonamide group (compound 4k) retained high enzymatic potency (IC50= 13.5 nM)). In cellular assays against blood-stage P. falciparum (3D7 strain), the leading depeptidized boronic acids exhibited growth inhibition with values in the low-micromolar range suggesting that further structural modifications are needed to enhance membrane permeability across host and parasite membranes to reach exonemes prior to egress. Overall, this study validates the P1-P2 depeptidization of boronic acid scaffolds and provides key SAR insights for the rational design of non-peptidic PfSUB1-targeted antimalarials.
ER -