Synthesis of Gallinamide A Analogues as Potent Falcipain Inhibitors and Antimalarials

Conroy, Trent; Guo, Jin; Elias, Nabiha; Cergol, Katie M.; Gut, Jiří; Legac, Jennifer; Khatoon, Lubna; Liu, Yang; McGowan, Sheena; Rosenthal, Philip J.; Hunt, Nicholas H.; Payne, Richard J.

doi:10.1021/jm501439w

Cited by 51 publications

(78 citation statements)

References 32 publications

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“…P. falciparum falcipain-2 inhibitors were compiled from literature. A total of 515 compounds previously assayed against falcipain-2 were collected from over 20 original articles, conforming the dataset used for model calibration and validation (Domínguez et al, 1997; Chiyanzu et al, 2003; Shenai et al, 2003; Desai et al, 2004, 2006; Greenbaum et al, 2004; Fujii et al, 2005; Goud et al, 2005; Micale et al, 2006; Valente et al, 2006; Biot et al, 2007; Chipeleme et al, 2007; Li et al, 2009; Hans et al, 2010; Praveen Kumar et al, 2011; Shah et al, 2011; Huang et al, 2012; Luo et al, 2012; Conroy et al, 2014; Ettari et al, 2014; Jin et al, 2014; Wang et al, 2014; Weldon et al, 2014; Bertoldo et al, 2015; Mundra and Radhakrishnan, 2015a,b; Sharma et al, 2015; Singh et al, 2015; Schmidt et al, 2016). Such compounds were labeled as ACTIVE or INACTIVE according to their reported inhibitory data.…”

Section: Methodsmentioning

confidence: 99%

In silico Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2

et al. 2019

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Malaria is among the leading causes of death worldwide. The emergence of Plasmodium falciparum resistant strains with reduced sensitivity to the first line combination therapy and suboptimal responses to insecticides used for Anopheles vector management have led to renewed interest in novel therapeutic options. Here, we report the development and validation of an ensemble of ligand-based computational models capable of identifying falcipain-2 inhibitors, and their subsequent application in the virtual screening of DrugBank and Sweetlead libraries. Among four hits submitted to enzymatic assays, two (odanacatib, an abandoned investigational treatment for osteoporosis and bone metastasis, and the antibiotic methacycline) confirmed inhibitory effects on falcipain-2, with Ki of 98.2 nM and 84.4 μM. Interestingly, Methacycline proved to be a non-competitive inhibitor (α = 1.42) of falcipain-2. The effects of both hits on falcipain-2 hemoglobinase activity and on the development of P. falciparum were also studied.

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Section: Methodsmentioning

confidence: 99%

In silico Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2

et al. 2019

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“…Promising nonpeptidyl falcipain inhibitors have included a series of nitriles that was extensively studied with many promising features, including excellent in vitro and in vivo potency [ 127 ]; this project was halted because of tissue binding that might predict idiosyncratic toxicity, but the evaluation of nitrile inhibitors is ongoing. Another interesting approach is the optimization of natural products, including analogues of gallinamide A, a compound from cyanobacteria with nanomolar antimalarial activity [ 128 ], and sugarcane cystatin [ 129 ].…”

Section: Introductionmentioning

confidence: 99%

Cysteine proteases in protozoan parasites

et al. 2018

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Cysteine proteases (CPs) play key roles in the pathogenesis of protozoan parasites, including cell/tissue penetration, hydrolysis of host or parasite proteins, autophagy, and evasion or modulation of the host immune response, making them attractive chemotherapeutic and vaccine targets. This review highlights current knowledge on clan CA cysteine proteases, the best-characterized group of cysteine proteases, from 7 protozoan organisms causing human diseases with significant impact: Entamoeba histolytica, Leishmania species (sp.), Trypanosoma brucei, T. cruzi, Cryptosporidium sp., Plasmodium sp., and Toxoplasma gondii. Clan CA proteases from three organisms (T. brucei, T. cruzi, and Plasmodium sp.) are well characterized as druggable targets based on in vitro and in vivo models. A number of candidate inhibitors are under development. CPs from these organisms and from other protozoan parasites should be further characterized to improve our understanding of their biological functions and identify novel targets for chemotherapy.

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“…Following initial loading and during peptide assembly, constant loading or a slight progressive decrease in loading has been described as an indication of good progress of synthesis . After cleavage of the peptide from the solid support, synthetic yields are typically reported based on the loading of the initial anchored unit . Resin loading can be estimated spectrophotometrically with ultraviolet–visible (UV–Vis) spectroscopy‐using methods based on DBU/DMF and dibenzofulvene (DBF) generation or piperidine/DMF and DBF‐piperidine adduct (λ max ≈ 267 nm, 290 nm, 301 nm) generation …”

Section: Introductionmentioning

confidence: 99%

Regeneration of aged DMF for use in solid‐phase peptide synthesis

Magtaan¹,

Devocelle

Kelleher³

2018

Journal of Peptide Science

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Dimethylformamide (DMF), which is still the most commonly used solvent for Fmoc-SPPS, has the potential for degradation over time on exposure to air (and water vapour) and storage, to give dimethylamine and formic acid impurities. In particular, dimethylamine can lead to unwanted deprotection of the fluorenylmethyloxycarbonyl (Fmoc) group during, for example, the initial loading of Fmoc amino acids in SPPS, which leads reduced calculated loading values. We have found that treatment of such aged DMF by simple sparging with an inert gas (N 2 ), or vacuum sonication, can regenerate the DMF in order to restore loading levels back to those found for newer, fresh, DMF samples.

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Synthesis of Gallinamide A Analogues as Potent Falcipain Inhibitors and Antimalarials

Cited by 51 publications

References 32 publications

In silico Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2

In silico Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2

Cysteine proteases in protozoan parasites

Regeneration of aged DMF for use in solid‐phase peptide synthesis

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