Exploiting ER proteostasis in malaria: protein disulphide isomerases as selective antimalarial targets.

In silico identification of selective cyclodecapeptide inhibitors targeting Plasmodium falciparum Grp78 chaperone

The increase in drug resistance by Plasmodium falciparum (Pf) remains a major challenge in eradicating malaria. The parasite drug resistance towards first line antimalarial therapy is associated with the parasite response to drug induced endoplasmic reticulum (ER) stress. The ER resident glucose-regulated protein 78 (PfGrp78) has been implicated as an ER stress response sensor. PfGrp78 binds to stressed protein substrates to suppress their misfolding and increase the capacity of the parasite ER to maintain proteostasis for parasite survival under stress. However, there have been limited efforts to target the parasite ER protein folding system as a potential drug target. This study sought to identify peptides that mimic the substrates of PfGrp78, which can be potential inhibitors of PfGrp78. Using the chaperone-substrate relationship, we explored the mechanism of action of cyclodecapeptides, gramicidin S (GS) and tyrocidines (Trcs), which were previously shown to exhibit potent antimalarial activity. In this study, using molecular docking and molecular dynamics simulation predictions, we observed that cyclodecapeptides bind to a unique site, suggesting preferential binding towards the substrate binding domain of PfGrp78 (β-SBD). The predicted binding site comprised the arch and pocket residues Gly426 to Thr446 and Pro455 to Val457, respectively. Furthermore, our extensive thermodynamics simulations supported the stable binding of the peptides and unveiled distinct inhibitory mechanisms. Our analysis suggests that the anti-plasmodial cyclodecapeptides, TrcA and GS, are predicted to act by inducing conformational locking, which may restrict the dynamic flexibility essential for the PfGrp78 chaperone cycle. Taken together, our results predict preferential binding of the cyclodecapeptides to PfGrp78 over its parasite cytosolic isoform and the human homologs. This offers promise for more experimental validation towards defining the molecular mechanism of action of these compounds.

PROTAC-Based Strategies in Neurodegenerative Diseases: Challenges and Perspectives

This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development.

Deconstruction of Aspartic Protease Inhibitors Enables Fragment‐Based Discovery of Plasmepsin V Inhibitors

Malaria, caused by the Plasmodium parasites, remains a major global health burden, and resistance to current antimalarials drives the need for drugs with new mechanisms of action. Plasmepsin V (PMV), an essential aspartic protease required for PEXEL processing and protein export, is structurally divergent from human aspartic proteases, offering a path to selective inhibition. Here, we applied a structure‐informed, deconstruction‐based approach to identify non‐peptidomimetic PMV inhibitors by mining catalytic dyad‐binding motifs from experimentally solved aspartic protease–inhibitor complexes and assembling a focused fragment‐like library. Fragment‐inspired model compounds based on pyrrolidine, piperidine, and piperazine cores showed measurable PMV inhibition in a Forster resonance energy transfer (FRET)‐based assay, and a trans‐3,4‐disubstituted pyrrolidine hit (7a; IC50 70  µM) was selected for optimization. Guided by PMV structural data and a renin cocrystal structure of a related pyrrolidine inhibitor, we explored SAR around substituents intended to engage the S1 and S2 regions. Optimization identified N‐sulfonamide analogs bearing two aromatic substituents as a preferred chemotype, with meta‐substitution on the N‐aryl group improving potency to the low micromolar range. The most potent compounds obtained displayed ~10 µM potency, establishing a promising non‐peptidomimetic scaffold for further development of selective PMV inhibitors.

Structure − Activity Relationship Study of Antimalarial Asparagine-Derived Proteasome Inhibitors

Revisiting Glutathione Transferases of Plasmodium as Potential Targets for Coadjuvant Therapies and the Development of New Antimalarials

Malaria remains a major global health problem, especially in low- and mid-income countries where Plasmodium parasites are commonly endemic. Despite the significant number of available drugs to treat the disease, some aspects, such as increasing resistance to frontline antimalarials, inefficient treatment of asymptomatic carriers and treatment inadequacy for certain vulnerable groups, are jeopardizing control measures, justifying the need for therapeutic targets driving the discovery of new compounds. In this context, glutathione transferases, which are essential for redox metabolism and detoxification of heme in the asexual blood stages of Plasmodium parasites, have emerged as promising targets more than two decades ago, but have been deprioritized due to significant gaps in research. This review aims to synthesize current biochemical, structural, genetic, and transcriptomic evidence on Plasmodium glutathione S-transferases and evaluate their role in parasite physiology across the life cycle while revising their potential for drug targeting using suggested guidelines for target candidate profiling and prioritization.

Why Not Now? Targeting Plasmodium falciparum histone methyltransferases for next-generation antimalarial strategies.

Plasmodium falciparum is the major human malaria parasite and its treatment remains challenging, with current artemisinin-based combination therapies increasingly compromised by emerging resistance in several regions. Although the pre-erythrocytic vaccines, Mosquirix and R21, are recommended only for children under five years of age in highly endemic African regions, their protective efficacy is moderate and wanes over time, underscoring the continued need for effective antimalarial drugs. Epigenetic mechanisms play a central role in regulating the parasite genome in response to diverse host environments, with methyltransferases acting as key components that dynamically modulate chromatin structure to control stage-specific gene expression. These epigenetic factors critically shape parasite fate by governing the expression of surface antigens, including var, RIFINs and STEVORs, thereby enabling immune evasion and the establishment of chronic infections. To date, no therapeutics specifically targeting histone lysine methyltransferases (HKMTs) have reached clinical use, although BIX-01294 has been explored as a candidate antimalarial in preclinical studies. This review synthesizes current knowledge on Plasmodium HKMTs, highlighting their biochemical activities, regulatory roles, and contributions to virulence. While evaluating emerging epigenetic inhibitors as potential antimalarial agents. We further discuss the main challenges in developing such therapies, emphasizing the necessity of detailed structural characterization, optimized pharmacological properties and rigorous validation of candidate compounds across Plasmodium species to enable successful translation.