Constrained peptidomimetics as antiplasmodial falcipain-2 inhibitors

Bova, Floriana; Ettari, Roberta; Micale, Nicola; Carnovale, Caterina; Schirmeister, Tanja; Gelhaus, Christoph; Leippe, Matthias; Grasso, Silvana; Zappalà, Maria

doi:10.1016/j.bmc.2010.06.010

Cited by 32 publications

(19 citation statements)

References 26 publications

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“…While many peptide‐based FP‐2 inhibitors were developed, their ability to be pursued as a therapeutic was limited due to their lack of cell permeation and susceptibility to proteolytic cleavage. To mimic the structural characteristics of a β‐turn and improve the pharmacokinetic properties of the peptide, a benzodiazepine scaffold was used as a structural base to develop novel FP‐2 peptidomimetic inhibitors . In this case, the benzodiazepine scaffold was incorporated into a dipeptide sequence that was designed to form an alkylated enzyme by covalently trapping the thiol group of the active site cysteine.…”

Section: Peptidomimetics Targeting Falcipain‐2mentioning

confidence: 99%

“…In this case, the benzodiazepine scaffold was incorporated into a dipeptide sequence that was designed to form an alkylated enzyme by covalently trapping the thiol group of the active site cysteine. These peptides exhibited significant inhibition of FP‐2 with IC 50 values in the low micromolar range and abolished enzyme activity . When tested against other nontarget cysteine proteases, the peptidomimetics exhibited no inhibitory activity, indicating good target selectivity …”

Section: Peptidomimetics Targeting Falcipain‐2mentioning

confidence: 99%

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TargetingPlasmodiumwith constrained peptides and peptidomimetics

Helton

Kennedy

2020

IUBMB Life

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Malaria remains a worldwide health concern with an estimated quarter of a billion people infected and nearly half a million deaths annually. Malaria is caused by a parasite infection from Plasmodium strains which are transmitted from mosquitoes into the human host. Although several small molecule inhibitors have been found to target the early stages of transmission and prevent parasite proliferation, multiple drug resistant parasite strains have emerged and drug resistance remains a major hurdle. As an alternative to small molecule inhibition, several peptide-based therapeutics have been explored for their potential as antimalarial compounds. Chemically constrained peptides or peptidomimetics were developed to target large binding interfaces of parasite-based proteins that have historically been difficult to selectively inhibit using small molecules. Here, we review ongoing research aimed at developing constrained peptides targeting protein-protein interactions pertinent to malaria pathogenesis. These targets include Falcipain-2, the J domain of CDPK1, myosin A tail domain interacting protein, the PKA signaling pathway, and an unclear signaling pathway involving angiotensin-derived peptides. Diverse synthetic methods were also used for each target. Merging parasite biology with synthetic strategies may provide new opportunities to develop alternative methods for uncovering novel antimalarials and may offer an alternate source for targeting drug-resistant parasite strains.

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Section: Peptidomimetics Targeting Falcipain‐2mentioning

confidence: 99%

Section: Peptidomimetics Targeting Falcipain‐2mentioning

confidence: 99%

TargetingPlasmodiumwith constrained peptides and peptidomimetics

Helton

Kennedy

2020

IUBMB Life

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“…In this context, our research group has been involved in the last years into the development of cysteine protease inhibitors for the treatment of NTDs [5][6][7][8][9][10][11][12][13][14]. In particular, we focused our attention on the design of peptidomimetics whose use, with respect to peptides, is particularly advantageous in terms of potency and selectivity, as widely demonstrated in these years by our group within the development of protease inhibitors [15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 97%

NMR conformational analysis in solution of a potent class of cysteine proteases inhibitors

et al. 2015

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Conformational analysis of a potent class of cysteine protease inhibitors is thoroughly studied by NMR, in both, polar and apolar solvents to get a better insight over the known biological activity and migration through biological media. These molecules are composed by a benzodiazepine (BDZ) scaffold connected to a bromoisoxazoline (IOX) ring through an alkyl spacer (AS) with up to four-carbon atoms. Data, supported by theoretical calculations at DFT level, reveal that both BDZ and IOX keep a pretty rigid and asymmetric conformation, so that four diastereo-atropisomers (two mirror-image couples) are generated. The relative stiffness of these substrates, maintained also in different solvents, is confirmed by: (a) remarkable separation of diastereotopic protons; (b) specific ''through the space contacts'' (NOESY); and (c) very good fitting of the coupling constants evaluations. The prototypic compound with the longer AS shows two main conformations and a certain dynamic freedom around the AS torsional angles close to IOX; according to our data, the AS length is not fundamental for the functional BDZ and IOX fitting into the macromolecular complex; however, it does play a crucial role to cross the parasite cell membranes.

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“…Diazepine ring system modified at N and three‐position has been studied extensively. They have been tested clinically as an antitrypanosomal activity , antiplasmodial falcipain‐2 inhibitors , antileukemic agents , and endothelin receptor antagonists . V. I. Pavlovsky et al .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Characterization of 1, 3‐disubstituted‐1,4‐benzodiazepine Derivatives

Ghelani

Naliapara

2015

Journal of Heterocyclic Chem

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The 2‐amino‐4′‐flouro‐benzophenone (1) that was reacted with chloroacetylchloride to afford 2‐chloro‐N‐(2‐(4′‐fluorobenzoyl) phenyl)acetamide (2) was subsequently converted to 1,4‐benzodiazepines (3) by the modification of the known hexamethylenetetramine based cyclization reaction developed by Blazevic and Kajfez. Thus, obtained product (3) was reacted with a variety of alkyl halide using KOH in DMF to give 1‐substituted‐5‐(4‐fluorophenyl)‐1H‐benzo[e][1,4]diazepin‐2(3H)‐one (4a, 4b). To achieve 1, 3‐disubstituted 1, 4‐benzodiazepines (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m, 5n, 5o, 5p, 5q, 5r, 5s, 5t), 1‐substituted‐5‐(4‐fluorophenyl)‐1H‐benzo[e][1,4]diazepin‐2(3H)‐one (4a, 4b) was treated with various aromatic aldehydes in the presence of KOH in toluene.

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Constrained peptidomimetics as antiplasmodial falcipain-2 inhibitors

Cited by 32 publications

References 26 publications

TargetingPlasmodiumwith constrained peptides and peptidomimetics

TargetingPlasmodiumwith constrained peptides and peptidomimetics

NMR conformational analysis in solution of a potent class of cysteine proteases inhibitors

Design, Synthesis, and Characterization of 1, 3‐disubstituted‐1,4‐benzodiazepine Derivatives

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