Branched pentapeptides as potent inhibitors of the vascular endothelial growth factor 165 binding to Neuropilin-1: Design, synthesis and biological activity
PBN-AR
Instytucja
Wydział Chemii (Uniwersytet Warszawski)
Informacje podstawowe
Główny język publikacji
en
Czasopismo
European Journal of Medicinal Chemistry (40pkt w roku publikacji)
ISSN
0223-5234
EISSN
Wydawca
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI
URL
Rok publikacji
2018
Numer zeszytu
Strony od-do
453-462
Numer tomu
158
Link do pełnego tekstu
Identyfikator DOI
Liczba arkuszy
Słowa kluczowe
en
Neuropilin-1
VEGF165
Neuropilin/VEGF165 binding inhibition
Structure-activity relationship
Peptide biostability
Streszczenia
Język
en
Treść
The demonstrated involvement of VEGF165/NRP-1 complex in pathological angiogenesis has catalyzed interest in blocking this interaction to combat angiogenesis dependent diseases. It was shown before that Lys-Pro-Pro-Arg is a fairly strong inhibitor of the VEGF165/NRP-1 interaction. Our current findings suggest that the side chain elongation of the Lys1 by branching it with additional homoarginine (Har) residue, to obtain Lys(Har)-Pro-Pro-Arg, allows more effective inhibition. Moreover, increasing the flexibility of the middle part of molecule, in particular with simultaneous introduction of additional interacting elements at the second or third position, produced compounds up to 30-fold more active (IC50 ¼ 0.2 mM) than the heptapeptide ATWLPPR (A7R) which is one of the first peptide known as an effective antagonist of the VEGF165 binding to NRP-1 and in vivo decreases breast cancer angiogenesis and growth. Herein, we present also the structure-activity study of Lys(Har)-Pro-Pro-Arg, discussing the design, synthesis, inhibitory activity, proteolytic stability and molecular modeling of the prepared derivatives. For two of the most active analogs the high proteolytic stability was also observed. These studies provide the next step for elucidating the optimal structure of the small peptidic inhibitors of VEGF165/NRP-1 interaction that could serve as research tools or be prospective drug candidates.
Cechy publikacji
Original article
Original article presents the results of original research or experiment.
Oryginalny artykuł naukowy
Oryginalny artykuł naukowy przedstawia rezultaty oryginalnych badań naukowych lub eksperymentu.
Inne
System-identifier
PX-5c4c2bc2d5defe0a4261facc
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