Structural studies of Enterococcus faecalis methionine aminopeptidase and design of microbe specific 2,2′-bipyridine based inhibitors

Kishor, Chandan; Gumpena, R.; Reddi, Ravikumar; Addlagatta, A.

doi:10.1039/c2md20096a

Cited by 18 publications

(13 citation statements)

References 32 publications

(27 reference statements)

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“…(human MetAPs) and Kishor et al. ( Enterococcus faecalis MetAP) suggested that noncovalent MetAP inhibition is strongly dependent on the appropriate orientation of nitrogen atoms for the correct formation of the inhibition complex. Kishor et al.…”

Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

“…Kishor et al. further postulated that class‐specific MetAP inhibitors could be generated through subtle modifications to both pyridine rings . This was later supported by an X‐ray crystallographic study between E. faecalis type 1a, human type 1b and Mycobacterium tuberculosis type 1c, which identified binding hotspots within the entrance to the active site, which could be exploited for the purposes of selectivity .…”

Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

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Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

Section: Kinetoplastids (Trypanosomiasis and Leishmaniasis)mentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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“…180° data in 1° oscillation was collected and processed in P 6 5 space group [16] (Table 2). Structure was solved by molecular replacement using the coordinates from E. feacalis MetAP ( Ef MetAP1a) (PDB ID: 3TB5) [17,18]. Refinement and modeling were performed using the REFMAC and coot [19,20].…”

Section: Methodsmentioning

confidence: 99%

Discovery of a New Genetic Variant of Methionine Aminopeptidase from Streptococci with Possible Post-Translational Modifications: Biochemical and Structural Characterization

et al. 2013

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Protein N-terminal methionine excision is an essential co-translational process that occurs in the cytoplasm of all organisms. About 60-70% of the newly synthesized proteins undergo this modification. Enzyme responsible for the removal of initiator methionine is methionine aminopeptidase (MetAP), which is a dinuclear metalloprotease. This protein is conserved through all forms of life from bacteria to human except viruses. MetAP is classified into two isoforms, Type I and II. Removal of the map gene or chemical inhibition is lethal to bacteria and to human cell lines, suggesting that MetAP could be a good drug target. In the present study we describe the discovery of a new genetic variant of the Type I MetAP that is present predominantly in the streptococci bacteria. There are two inserts (insert one: 27 amino acids and insert two: four residues) within the catalytic domain. Possible glycosylation and phosphorylation posttranslational modification sites are identified in the ‘insert one’. Biochemical characterization suggests that this enzyme behaves similar to other MetAPs in terms of substrate specificity. Crystal structure Type Ia MetAP from Streptococcus pneumoniae (SpMetAP1a) revealed that it contains two molecules in the asymmetric unit and well ordered inserts with structural features that corroborate the possible posttranslational modification. Both the new inserts found in the SpMetAP1a structurally align with the P-X-X-P motif found in the M. tuberculosis and human Type I MetAPs as well as the 60 amino acid insert in the human Type II enzyme suggesting possible common function. In addition, one of the β-hairpins within in the catalytic domain undergoes a flip placing a residue which is essential for enzyme activity away from the active site and the β-hairpin loop of this secondary structure in the active site obstructing substrate binding. This is the first example of a MetAP crystallizing in the inactive form.

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“…The metalloprotease, methionine amino peptidase (MetAP), has been reported as a novel therapeutic target for infectious diseases. [3][4][5][6][7][8][9][10][11] It has been validated as a target for various infectious diseases caused by methicillinresistant Staphylococcus aureus and Escherichia coli, 3 Mycobacterium tuberculosis (Mtb), [4][5][6][7] Cryptosporidium parvum, 8 Plasmodium falciparum, 9 Leishmania donovani, 10 Enterococcus faecalis, 11,12 Rickettsia prowazekii, 13 and Acinetobacter baumannii. 14 It has also been investigated as a potential therapeutic target for several other diseases including cancer and rheumatoid arthritis.…”

Section: Introductionmentioning

confidence: 99%

<p>Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases</p>

Ekpenyong¹,

Gao²,

Ma³

et al. 2020

DDDT

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Introduction: CLBQ14, a derivative of 8-hydroxyquinoline, exerts its chemotherapeutic effect by inhibiting methionine aminopeptidase (MetAP), the enzyme responsible for the post-translational modification of several proteins and polypeptides. MetAP is a novel target for infectious diseases. CLBQ14 is selective and highly potent against replicating and latent Mycobacterium tuberculosis making it an appealing lead for further development. Methods: The physicochemical properties (solubility, pH stability and lipophilicity), in vitro plasma stability and metabolism, pre-clinical pharmacokinetics, plasma protein binding and tissue distribution of CLBQ14 in adult male Sprague-Dawley rats were characterized. Results: At room temperature, CLBQ14 is practically insoluble in water (<0.07 mg/mL) but freely soluble in dimethyl acetamide (>80 mg/mL); it has a log P value of 3.03 ± 0.04. CLBQ14 exhibits an inverse Z-shaped pH decomposition profile; it is stable at acidic pH but is degraded at a faster rate at basic pH. It is highly bound to plasma proteins (>91%), does not partition to red blood cells (B/P ratio: 0.83 ± 0.03), and is stable in mouse, rat, monkey and human plasma. CLBQ14 exhibited a bi-exponential pharmacokinetics after intravenous administration in rats, bioavailability of 39.4 and 90.0%, respectively from oral and subcutaneous route. We observed a good correlation between predicted and observed rat clearance, 1.90 ± 0.17 L/kg/h and 1.67 ± 0.08 L/kg/h, respectively. Human hepatic clearance predicted from microsomal stability data and from the single species scaling were 0.80 L/hr/kg and 0.69 L/h/kg, respectively. CLBQ14 is extensively distributed in rats; following a 5 mg/kg intravenous administration, lowest and highest concentrations of 15.6 ± 4.20 ng/g of heart and 405.9 ± 77.11 ng/g of kidneys, respectively, were observed. In vitro CYP reaction phenotyping demonstrates that CLBQ14 is metabolized primarily by CYP 1A2. Conclusion: CLBQ14 possess appealing qualities of a drug candidate. The studies reported herein are imperative to the development of CLBQ14 as a new chemical entity for infectious diseases.

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Structural studies of Enterococcus faecalis methionine aminopeptidase and design of microbe specific 2,2′-bipyridine based inhibitors

Cited by 18 publications

References 32 publications

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Discovery of a New Genetic Variant of Methionine Aminopeptidase from Streptococci with Possible Post-Translational Modifications: Biochemical and Structural Characterization

<p>Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases</p>

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