Discovery of novel competitive dihydropteridine reductase inhibitors via high throughput screening and their effect on metabolic pterin balance of fibroblast.

The development of tool compounds for the study of the tetrahydrobiopterin (BH4) metabolic network perturbation is of interest especially in the case of oxidative and nitrosative stress genesis. A semisynthetic FRET sensor was engineered in order to study competitive dihydropteridine reductase (DHPR) inhibition. A high-throughput screen, using the designed sensor, was performed on the Prestwick library to discover thirteen new competitively interacting small molecules. Triamterene (TRI), ebselen (EBS), adrenosterone (ADR) and deoxycorticosterone (DCS) were found to be the most potent inhibitors of this set. Their inhibition potency were assayed in-vitro on four of the members of the BH4 metabolic pathway, GTP cyclohydrolase I (GCH1), sepiapterin reductase (SPR), dihydrofolate reductase (DHFR) and DHPR. TRI was discovered to be the most active DHPR inhibitor and confirmed to be a potent DHFR binder. EBS showed potency in altering GCH1 and SPR catalytic activity probably by covalently modifying some of the catalytic cysteine residues. Finally, the drug candidates were assayed on adult human dermal fibroblast for their potency to influence the concentration ratios of BH4 and 7,8-dihydrobiopterin (BH2). Here, TRI showed to be the best candidate by reducing the basal BH4/BH2 ratio of ~15 to unity. This effect is more pronounced than that generated by other previously described DHPR inhibitors such as aminopterin. Finally, the observed pterin metabolic imbalance generated by TRI makes it a useful compound to investigate the relevance of BH4/BH2 imbalance.


Advisor(s):
Johnsson, Kai
Hatzimanikatis, Vassily
Year:
2018
Publisher:
Lausanne, EPFL
Keywords:
Laboratories:




 Record created 2018-01-17, last modified 2019-05-09

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