Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax

Hodder, Anthony N.; Christensen, Janni; Scally, S.W.; Triglia, Tony; Ngo, Anna; Birkinshaw, R.W.; Bailey, Brodie L; Favuzza, Paola; Dietrich, M.H.; Tham, Wai‐Hong; Czabotar, P.E.; Lowes, Kym N; Guo, Zhuyan; Murgolo, Nicholas; Ruiz, Manuel de Lera; McCauley, John A.; Sleebs, Brad E.; Olsen, David B.; Cowman, Alan F.

doi:10.1016/j.str.2022.03.018

Cited by 14 publications

(31 citation statements)

References 35 publications

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“…Weak inhibition of PMIX was unexpected because of the high homology and the similarities of the consensus sequence between these aspartyl proteases, although 49c ( 2 ) also displays the same selectivity profile, suggesting the P 1 ’ α‐methyl benzylamine motif contributes to selectivity. Potent dual inhibition of PMX and PMIX is plausible and is reported with the antimalarial tool compound WM382 (1) [27,28] . This is an attractive and adventitious attribute in curbing the onset of resistance, further supporting PMX as an attractive antimalarial target.…”

Section: Discussionmentioning

confidence: 88%

“…The data showed analogues 26 , 34 , 37 and 38 displayed weak activity against PMIX (IC 50 2.7–41 μM). This result is complexing because the substrate consensus sequence of PMIX (SFLE) is almost identical to the consensus sequence of PMX (SF h E), although PMIX does not cleave the same repertoire of substrates as PMX [27,28] . The binding pockets PMX and PMIX are highly homologous, although there are subtle differences in amino acid composition that may contribute to selectivity observed with the peptidomimetic compounds.…”

Section: Resultsmentioning

confidence: 99%

“…PMIX and PMX have high homology, and both are essential for asexual parasite development. PMIX is expressed in the late asexual blood stage and critically processes rhoptry associated proteins, such as rhoptry associated protein 1 (RAP1) and apical sushi protein (ASP) that mediate secretory function in merozoite invasion of the host erythrocyte (Figure S1) [25–27] . PMX processes surface invasion ligands, such as apical membrane protein 1 (AMA1) critical for parasite invasion of the erythrocyte [25,26,28] .…”

Section: Introductionmentioning

confidence: 99%

“…Positions of structural moieties of 38 are labelled relative to their respective binding pockets. PMX flap amino acids Ile274 to Ile281 were excluded for clarity, which includes the hydrogen bonds of Ser to Gly278 and Ser277 from PMX with the P 2 Ser of 38.The model was generated using the X-ray structure of the HEA compound MR0C 803 bound to BACE-1 (PDB: 2P83)[38] as a template for positioning the peptidomimetic 38 before performing minimalization with the X-ray structure of PMX (PDB: 72BC) [27].…”

mentioning

confidence: 99%

“…Ac-Asn-Ser-Phe-HEA-Bn(CH 3 )•TFA(27). General procedure F was followed with Ac-Asn(N-Trt)-Ser(OtBu)-Phe-HEA-Bn(CH 3 ) (20) (7.6 mg, 0.01 mmol) to give the title compound 27 (3.4 mg, 42 %) as a white solid 1.…”

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confidence: 99%

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Substrate Peptidomimetic Inhibitors of P. falciparum Plasmepsin X with Potent Antimalarial Activity

et al. 2022

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Plasmepsin X (PMX) is an aspartyl protease that processes proteins essential for Plasmodium parasites to invade and egress from host erythrocytes during the symptomatic asexual stage of malaria. PMX substrates possess a conserved cleavage region denoted by the consensus motif, SFhE (h=hydrophobic amino acid). Peptidomimetics reflecting the P3‐P1 positions of the consensus motif were designed and showed potent and selective inhibition of PMX. It was established that PMX prefers Phe in the P1 position, di‐substitution at the β‐carbon of the P2 moiety and a hydrophobic P3 group which was supported by modelling of the peptidomimetics in complex with PMX. The peptidomimetics were shown to arrest asexual P. falciparum parasites at the schizont stage by impairing PMX substrate processing. Overall, the peptidomimetics described will assist in further understanding PMX substrate specificity and have the potential to act as a template for future antimalarial design.

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Section: Discussionmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Substrate Peptidomimetic Inhibitors of P. falciparum Plasmepsin X with Potent Antimalarial Activity

et al. 2022

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Chemo‐proteomics in antimalarial target identification and engagement

Bailey

Nguyen

Cowman

et al. 2023

Medicinal Research Reviews

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Humans have lived in tenuous battle with malaria over millennia. Today, while much of the world is free of the disease, areas of South America, Asia, and Africa still wage this war with substantial impacts on their social and economic development. The threat of widespread resistance to all currently available antimalarial therapies continues to raise concern. Therefore, it is imperative that novel antimalarial chemotypes be developed to populate the pipeline going forward. Phenotypic screening has been responsible for the majority of the new chemotypes emerging in the past few decades. However, this can result in limited information on the molecular target of these compounds which may serve as an unknown variable complicating their progression into clinical development. Target identification and validation is a process that incorporates techniques from a range of different disciplines. Chemical biology and more specifically chemo‐proteomics have been heavily utilized for this purpose. This review provides an in‐depth summary of the application of chemo‐proteomics in antimalarial development. Here we focus particularly on the methodology, practicalities, merits, and limitations of designing these experiments. Together this provides learnings on the future use of chemo‐proteomics in antimalarial development.

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Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery

Mishra,

Deshmukh,

Rathore

et al. 2024

Current Research in Structural Biology

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Basis for drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax

Cited by 14 publications

References 35 publications

Substrate Peptidomimetic Inhibitors of P. falciparum Plasmepsin X with Potent Antimalarial Activity

Substrate Peptidomimetic Inhibitors of P. falciparum Plasmepsin X with Potent Antimalarial Activity

Chemo‐proteomics in antimalarial target identification and engagement

Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery

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