Structure-based drug design, synthesis and biological assays of P. falciparum Atg3–Atg8 protein–protein interaction inhibitors

Villa, Stefania; Legnani, Laura; Colombo, Diego; Gelain, Arianna; Lammi, Carmen; Bongiorno, Daniele; Ilboudo, D.; McGee, K.; Bosch, Jürgen; Grazioso, Giovanni

doi:10.1007/s10822-018-0102-5

Cited by 10 publications

(14 citation statements)

References 42 publications

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“…More recently, Villa et al finally developed new antimicrobial PPI inhibitors by applying computational techniques to the crystal structure of the ATG3 and ATG8 complex (PDB ID: 4EOY) [39,43]. The inhibitor is a peptidomimetic that mimics the ATG3 interaction motif and delays the blood and liver stages of parasite growth.…”

Section: Discussionmentioning

confidence: 99%

A Structural Approach into Drug Discovery Based on Autophagy

Kang

Kim

2021

Life

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Autophagy is a lysosome-dependent intracellular degradation machinery that plays an essential role in the regulation of cellular homeostasis. As many studies have revealed that autophagy is related to cancer, neurodegenerative diseases, metabolic diseases, and so on, and it is considered as a promising drug target. Recent advances in structural determination and computational technologies provide important structural information on essential autophagy-related proteins. Combined with high-throughput screening methods, structure-activity relationship studies have led to the discovery of molecules that modulate autophagy. In this review, we summarize the recent structural studies on autophagy-related proteins and the discovery of modulators, indicating that targeting autophagy can be utilized as an effective strategy for novel drug development.

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Section: Discussionmentioning

confidence: 99%

A Structural Approach into Drug Discovery Based on Autophagy

Kang

Kim

2021

Life

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“…Upon structural analysis of the interaction between Pf ATG8 and its cognate E2 Pf ATG3 in P. falciparum , the structural loop that mediates the interaction was discovered in Pf ATG8, but not in its human counterpart [ 126 ]. This distinguishing feature enabled the development of parasite-specific inhibitors that selectively block Pf ATG8- Pf ATG3 interaction in P. falciparum and inhibit parasite growth [ 126 , 127 , 128 , 129 ].…”

Section: Atg8 and Atg12: Moonlighting Autophagy Machinerymentioning

confidence: 99%

Ubiquitin-Like Modifiers: Emerging Regulators of Protozoan Parasites

Karpiyevich

Artavanis‐Tsakonas

2020

Biomolecules

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Post-translational protein regulation allows for fine-tuning of cellular functions and involves a wide range of modifications, including ubiquitin and ubiquitin-like modifiers (Ubls). The dynamic balance of Ubl conjugation and removal shapes the fates of target substrates, in turn modulating various cellular processes. The mechanistic aspects of Ubl pathways and their biological roles have been largely established in yeast, plants, and mammalian cells. However, these modifiers may be utilised differently in highly specialised and divergent organisms, such as parasitic protozoa. In this review, we explore how these parasites employ Ubls, in particular SUMO, NEDD8, ATG8, ATG12, URM1, and UFM1, to regulate their unconventional cellular physiology. We discuss emerging data that provide evidence of Ubl-mediated regulation of unique parasite-specific processes, as well as the distinctive features of Ubl pathways in parasitic protozoa. We also highlight the potential to leverage these essential regulators and their cognate enzymatic machinery for development of therapeutics to protect against the diseases caused by protozoan parasites.

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“…MD simulations revealed several crucial PPIs including H-bonds, van der Walls contacts, and other electrostatic interactions that are crucial for their interactions. Crucially, a peptidomimetic compound mimicking the PfAtg3 segment WLLP that interacts with PfAtg8 was identified to achieve maximum potency [37].…”

Section: Protein Exportmentioning

confidence: 99%

“…These compounds mimicked the contacts made by PfAtg3 template structure containing the residues W-L-L-P, as this template was shown to have the majority of interactions with PfAtg8. Of the four compounds synthesized, compound 2 (C2) exhibited prominent inhibition (IC 50 -3.8 μM) in vitro, while C1 had better inhibitory effects in vivo [37].…”

Section: Ppi Inhibition: Peptidomimetics and Designmentioning

confidence: 99%

Protein-Protein Interactions in Malaria: Emerging Arena for Future Chemotherapeutics

Pasupureddy¹,

Seshadri²,

Dixit³

et al. 2020

Parasitology and Microbiology Research

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Malaria is one of the most deadly diseases infecting humans. Advances in elimination and vector control have reduced the global malaria burden in the past decade; however, the emerging threat of drug resistance and suboptimal vaccine efficacies threaten global eradication efforts. Unlocking novel drug and vaccine targets while simultaneously mitigating spread of resistant strains seems to be the need of the hour. Protein-protein interactions (PPIs), an integral part of hostpathogen cross-talk and parasite survival, have only recently emerged as promising drug targets. Large PPI networks (interactome) are being developed to better our understanding of various parasite biochemical pathways. In this chapter, we throw light on several newly characterized protein-protein interactions between the host (humans) and parasite (plasmodium) in key processes such as hemoglobin degradation, enzyme regulation, protein export, egress, invasion, and drug resistance and further discuss their viability for development as novel chemotherapeutic targets.

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Structure-based drug design, synthesis and biological assays of P. falciparum Atg3–Atg8 protein–protein interaction inhibitors

Cited by 10 publications

References 42 publications

A Structural Approach into Drug Discovery Based on Autophagy

A Structural Approach into Drug Discovery Based on Autophagy

Ubiquitin-Like Modifiers: Emerging Regulators of Protozoan Parasites

Protein-Protein Interactions in Malaria: Emerging Arena for Future Chemotherapeutics

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