Peptide-Conjugated Pterins as Inhibitors of Ricin Toxin A

Saito, Ryota; Pruet, Jeff M.; Manzano, L.A.; Jasheway, K.R.; Monzingo, A.F.; Wiget, Paul A.; Kamat, Ishan; Anslyn, Eric V.; Robertus, Jon D.

doi:10.1021/jm3016393

Cited by 25 publications

(39 citation statements)

References 38 publications

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“…Assays that directly measure depurination activity for toxin detection and mitigation procedures were recently reviewed [ 29 , 30 ]. Here, we specifically review the assays, which identified differences in the activity of Stxs [ 31 ], differences in ribosome interactions of RTA [ 22 , 32 , 33 , 34 , 35 , 36 ], Stxs [ 21 , 22 , 37 ], TCS [ 23 , 26 ], and PAP [ 24 , 25 ], provided information about the downstream consequences of depurination, such as the ribotoxic stress response and apoptosis [ 38 , 39 , 40 ], allowed the use of RIPs as tools to probe the structure and function of the ribosomal stalk [ 41 ], provided information about the functional divergence of the ribosomal stalk P1-P2 dimers [ 42 ] and were useful in the search for RIP inhibitors [ 43 , 44 , 45 , 46 , 47 , 48 ]. We discuss the advantages and limitations of each method and explain how more sensitive assays can distinguish the differences in depurination activity and provide information about the kinetics and the mechanism of the depurination reaction.…”

Section: Introductionmentioning

confidence: 99%

Functional Assays for Measuring the Catalytic Activity of Ribosome Inactivating Proteins

Zhou

Kahn

et al. 2018

Toxins

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Ribosome-inactivating proteins (RIPs) are potent toxins that inactivate ribosomes by catalytically removing a specific adenine from the α-sarcin/ricin loop (SRL) of the large rRNA. Direct assays for measuring depurination activity and indirect assays for measuring the resulting translation inhibition have been employed to determine the enzyme activity of RIPs. Rapid and sensitive methods to measure the depurination activity of RIPs are critical for assessing their reaction mechanism, enzymatic properties, interaction with ribosomal proteins, ribotoxic stress signaling, in the search for inhibitors and in the detection and diagnosis of enteric infections. Here, we review the major assays developed for measuring the catalytic activity of RIPs, discuss their advantages and disadvantages and explain how they are used in understanding the catalytic mechanism, ribosome specificity, and dynamic enzymatic features of RIPs.

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Section: Introductionmentioning

confidence: 99%

Functional Assays for Measuring the Catalytic Activity of Ribosome Inactivating Proteins

Zhou

Kahn

et al. 2018

Toxins

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“…Furthermore, point mutations and (or) oxidative damage of proteins can result in increased surface hydrophobicity of proteins and have been linked to several age-related proteinopathies 7 8 9 10 11 12 . As a result, there has been a growing interest and need for developing probes and methods for sensing protein surface hydrophobicity 13 14 15 16 17 as this can help to design better drug molecules based on surface properties 18 19 20 21 .…”

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confidence: 99%

BODIPY-Based Fluorescent Probes for Sensing Protein Surface-Hydrophobicity

Dorh

Zhu

Dhungana

et al. 2015

Sci Rep

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Mapping surface hydrophobic interactions in proteins is key to understanding molecular recognition, biological functions, and is central to many protein misfolding diseases. Herein, we report synthesis and application of new BODIPY-based hydrophobic sensors (HPsensors) that are stable and highly fluorescent for pH values ranging from 7.0 to 9.0. Surface hydrophobic measurements of proteins (BSA, apomyoglobin, and myoglobin) by these HPsensors display much stronger signal compared to 8-anilino-1-naphthalene sulfonic acid (ANS), a commonly used hydrophobic probe; HPsensors show a 10- to 60-fold increase in signal strength for the BSA protein with affinity in the nanomolar range. This suggests that these HPsensors can be used as a sensitive indicator of protein surface hydrophobicity. A first principle approach is used to identify the molecular level mechanism for the substantial increase in the fluorescence signal strength. Our results show that conformational change and increased molecular rigidity of the dye due to its hydrophobic interaction with protein lead to fluorescence enhancement.

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“…An equal strategy as the one followed to find aldose reductase inhibitors (see previous Section , diabetes complications) was also used by the same research group against RTA. They synthesized several dipeptides and tripeptides conjugated to pterin‐7‐carboxamides and obtained good results in RTA inhibition assays, with IC 50 values ranging from 6 to 115 μM, with the tyrosine‐conjugated compound 78 being the most potent molecule (Table ) …”

Section: Other Activitiesmentioning

confidence: 99%

Therapeutic potential of pteridine derivatives: A comprehensive review

Carmona‐Martínez

Ruiz–Alcaraz

Vera

et al. 2018

Medicinal Research Reviews

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Pteridines are aromatic compounds formed by fused pyrazine and pyrimidine rings. Many living organisms synthesize pteridines, where they act as pigments, enzymatic cofactors, or immune system activation molecules. This variety of biological functions has motivated the synthesis of a huge number of pteridine derivatives with the aim of studying their therapeutic potential. This review gathers the state‐of‐the‐art of pteridine derivatives, describing their biological activities and molecular targets. The antitumor activity of pteridine‐based compounds is one of the most studied and advanced therapeutic potentials, for which several molecular targets have been identified. Nevertheless, pteridines are also considered as very promising therapeutics for the treatment of chronic inflammation‐related diseases. On the other hand, many pteridine derivatives have been tested for antimicrobial activities but, although some of them resulted to be active in preliminary assays, a deeper research is needed in this area. Moreover, pteridines may be of use in the treatment of many other diseases, such as diabetes, osteoporosis, ischemia, or neurodegeneration, among others. Thus, the diversity of the biological activities shown by these compounds highlights the promising therapeutic use of pteridine derivatives. Indeed, methotrexate, pralatrexate, and triamterene are Food and Drug Administration approved pteridines, while many others are currently under study in clinical trials.

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Peptide-Conjugated Pterins as Inhibitors of Ricin Toxin A

Cited by 25 publications

References 38 publications

Functional Assays for Measuring the Catalytic Activity of Ribosome Inactivating Proteins

Functional Assays for Measuring the Catalytic Activity of Ribosome Inactivating Proteins

BODIPY-Based Fluorescent Probes for Sensing Protein Surface-Hydrophobicity

Therapeutic potential of pteridine derivatives: A comprehensive review

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