Identification of the Molecular Basis of Inhibitor Selectivity between the Human and Streptococcal Type I Methionine Aminopeptidases

Arya, T.; Reddi, Ravikumar; Kishor, Chandan; Ganji, Roopa Jones; Bhukya, Supriya; Gumpena, R.; McGowan, Sheena; Drąg, Marcin; Addlagatta, A.

doi:10.1021/jm501790e

Cited by 21 publications

(8 citation statements)

References 39 publications

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“…The root mean squared difference (r.m.s.d.) of the core 250 residue ‘pita bread’ fold between the R. prowazekii MetAP as compared to Pseudomonas aeruginosa (PDB: 4FO7), E. coli (PDB: 1XNZ 12 ) and Homo sapiens (PDB: 4U1B 13 ) was 0.985 Å, 0.711 Å, and 0.865 Å, respectively. For both the A4 and A6 RpMetAP structures, no divalent metal ion was included in the crystallization conditions.…”

Section: Resultsmentioning

confidence: 99%

Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents

Helgren

Chen

Wangtrakuldee

et al. 2017

Bioorganic & Medicinal Chemistry

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Methionine aminopeptidase (MetAP) is a class of ubiquitous enzymes essential for the survival of numerous bacterial species. These enzymes are responsible for the cleavage of N-terminal formyl-methionine initiators from nascent proteins to initiate post-translational modifications that are often essential to proper protein function. Thus, inhibition of MetAP activity has been implicated as a novel antibacterial target. We tested this idea in the present study by targeting the MetAP enzyme in the obligate intracellular pathogen Rickettsia prowazekii. We first identified potent RpMetAP inhibitory species by employing an in vitro enzymatic activity assay. The molecular docking program AutoDock was then utilized to compare published crystal structures of inhibited MetAP species to docked poses of RpMetAP. Based on these in silico and in vitro screens, a subset of 23 compounds was tested for inhibition of R. prowazekii growth in a pulmonary vascular endothelial cell (EC) culture infection model system. All compounds were tested over concentration ranges that were determined to be non-toxic to the ECs and 10 of the 23 compounds displayed substantial inhibition of R. prowazekii growth. These data highlight the therapeutic potential for inhibiting RpMetAP as a novel antimicrobial strategy and set the stage for future studies in pre-clinical animal models of infection.

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Section: Resultsmentioning

confidence: 99%

Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents

Helgren

Chen

Wangtrakuldee

et al. 2017

Bioorganic & Medicinal Chemistry

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“…From the 13 potential drug targets, 10 were includes despite not passing the homology or druggability filters of the PBIT pipeline ( Tables 1 and 2 , and Table S15 ). The problem of having homology with the human proteome or human gut microbiota proteome can be solved by screening compounds that selectively inhibit the pathogen protein ( Arya et al, 2015 ). The druggability prediction of the PBIT pipeline is based on sequence similarity to experimentally validated targets ( Shende et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…tyrS was predicted as a virulence factor and an ortholog from Pseudomonas aeruginosa was found to be targeted by four drug-like compounds ( Hughes et al, 2020 ), and a S. aureus ortholog to this gene was targeted by new pyrazolone and dipyrazolotriazine derivatives ( Othman et al, 2021 ). mapB from M. tuberculosis and S. pneumoniae were shown to be selectively targeted despite homology to human protein ( Krátký et al, 2012 ; Arya et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Evidence of episodic positive selection in Corynebacterium diphtheriae complex of species and its implementations in identification of drug and vaccine targets

Viana

Profeta

Cerqueira

et al. 2022

PeerJ

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Background Within the pathogenic bacterial species Corynebacterium genus, six species that can produce diphtheria toxin (C. belfantii, C. diphtheriae, C. pseudotuberculosis, C. rouxii, C. silvaticum and C. ulcerans) form a clade referred to as the C. diphtheria complex. These species have been found in humans and other animals, causing diphtheria or other diseases. Here we show the results of a genome scale analysis to identify positive selection in protein-coding genes that may have resulted in the adaptations of these species to their ecological niches and suggest drug and vaccine targets. Methods Forty genomes were sampled to represent species, subspecies or biovars of Corynebacterium. Ten phylogenetic groups were tested for positive selection using the PosiGene pipeline, including species and biovars from the C. diphtheria complex. The detected genes were tested for recombination and had their sequences alignments and homology manually examined. The final genes were investigated for their function and a probable role as vaccine or drug targets. Results Nineteen genes were detected in the species C. diphtheriae (two), C. pseudotuberculosis (10), C. rouxii (one), and C. ulcerans (six). Those were found to be involved in defense, translation, energy production, and transport and in the metabolism of carbohydrates, amino acids, nucleotides, and coenzymes. Fourteen were identified as essential genes, and six as virulence factors. Thirteen from the 19 genes were identified as potential drug targets and four as potential vaccine candidates. These genes could be important in the prevention and treatment of the diseases caused by these bacteria.

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“…Moreover, targeting nonactive sites makes self-derived peptides more specific because active sites of proteins such as MetAP are often conserved between bacteria and humans (42). In other words, structure-targeting peptides will be highly specific.…”

Section: Discussionmentioning

confidence: 99%

Self‐derived structure‐disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides

et al. 2018

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Bacterial infection is one of the leading causes of death in young, elderly, and immune‐compromised patients. The rapid spread of multi‐drug‐resistant (MDR) bacteria is a global health emergency and there is a lack of new drugs to control MDR pathogens. We describe a heretofore‐unexplored discovery pathway for novel antibiotics that is based on self‐targeting, structure‐disrupting peptides. We show that a helical peptide, KFF‐EcH3, derived from the Escherichia coli methionine aminopeptidase can disrupt secondary and tertiary structure of this essential enzyme, thereby killing the bacterium (including MDR strains). Significantly, no detectable resistance developed against this peptide. Based on a computational analysis, our study predicted that peptide KFF‐EcH3 has the strongest interaction with the structural core of the methionine aminopeptidase. We further used our approach to identify peptide KFF‐NgH1 to target the same enzyme from Neisseria gonorrhoeae. This peptide inhibited bacterial growth and was able to treat a gonococcal infection in a human cervical epithelial cell model. These findings present an exciting new paradigm in antibiotic discovery using self‐derived peptides that can be developed to target the structures of any essential bacterial proteins.—Zhan, J., Jia, H., Semchenko, E. A., Bian, Y., Zhou, A. M., Li, Z., Yang, Y., Wang, J., Sarkar, S., Totsika, M., Blanchard, H., Jen, F. E.‐C., Ye, Q., Haselhorst, T., Jennings, M. P., Scib, K. L., Zhou, Y. Self‐derived structure‐disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides. FASEB J. 33, 2095–2104 (2019). http://www.fasebj.org

show abstract

Identification of the Molecular Basis of Inhibitor Selectivity between the Human and Streptococcal Type I Methionine Aminopeptidases

Cited by 21 publications

References 39 publications

Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents

Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents

Evidence of episodic positive selection in Corynebacterium diphtheriae complex of species and its implementations in identification of drug and vaccine targets

Self‐derived structure‐disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides

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