Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin.
ChemMedChem
; 12(8): 613-620, 2017 04 20.
Article
in En
| MEDLINE
| ID: mdl-28334511
ABSTRACT
Novel elongated and shortened derivatives of the peptidomimetic furin inhibitor phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide were synthesized. The most potent compounds, such as Nα (carbamidoyl)Arg-Arg-Val-Arg-4-amidinobenzylamide (Ki =6.2â
pm), contain additional basic residues at the Nâ
terminus and inhibit furin in the low-picomolar range. Furthermore, to decrease the molecular weight of this inhibitor type, compounds that lack the P5 moiety were prepared. The best inhibitors of this series, 5-(guanidino)valeroyl-Val-Arg-4-amidinobenzylamide and its P3 tert-leucine analogue displayed Ki values of 2.50 and 1.26â
nm, respectively. Selected inhibitors, together with our previously described 4-amidinobenzylamide derivatives as references, were tested in cell culture for their activity against furin-dependent infectious pathogens. The propagation of the alphaviruses Semliki Forest virus and chikungunya virus was strongly inhibited in the presence of selected derivatives. Moreover, a significant protective effect of the inhibitors against diphtheria toxin was observed. These results confirm that the inhibition of furin should be a promising approach for the short-term treatment of acute infectious diseases.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oligopeptides
/
Benzamides
/
Serine Proteinase Inhibitors
/
Furin
/
Peptidomimetics
Limits:
Animals
Language:
En
Journal:
ChemMedChem
Journal subject:
FARMACOLOGIA
/
QUIMICA
Year:
2017
Document type:
Article