Integrin inhibitors from snake venom: exploring the relationship between the structure and activity of RGD-peptides.
alphaIIbbeta3 is an integrin that is involved in platelet adhesion and aggregation. This receptor may be inhibited by cysteine-rich peptides known as disintegrins. We isolated two disintegrins from Bothrops jararaca venom called jarastatin and jararacin. We evaluated the structural characteristics and the effects on human platelet aggregation of these disintegrins. Inhibitory profiles were compared to six distinct peptides synthesized based on their RGD hairpin loop primary sequences. Both jarastatin and jararacin inhibited ADP and thrombin induction. Conversely, none of the cyclic peptides showed high-quality activity in assays induced by ADP or thrombin. We constructed homology models for all of these molecules, and theoretically evaluated their interaction with the alphaIIbbeta3 crystal structure using a molecular modeling approach. These results support the observations that the cyclic peptides had little effects, and also reinforce the observation that residues outside the disintegrin RGD sequence are required for interactions with receptor.
Wermelinger
Luciana S
LS
Instituto de Bioquímica Médica, Programa de Biologia Estrutural, CCS, Universidade Federal Rio de Janeiro, CEP 21941-590, Rio de Janeiro, RJ, Brazil.
Geraldo
Reinaldo B
RB
Frattani
Flavia S
FS
Rodrigues
Carlos R
CR
Juliano
Maria A
MA
Castro
Helena C
HC
Zingali
Russolina B
RB
D000595:Amino Acid Sequence; D000818:Animals; D017837:Bothrops; D002851:Chromatography, High Pressure Liquid; D003435:Crotalid Venoms / Q000737:chemistry / Q000633:toxicity*; D019483:Disintegrins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D010974:Platelet Aggregation / Q000187:drug effects*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013917:Thrombin / Q000096:biosynthesis / Q000187:drug effects
D003435:Crotalid Venoms; D019483:Disintegrins; D016023:Integrins; D009842:Oligopeptides; D010455:Peptides; C121483:jarastatin; C047981:arginyl-glycyl-aspartic acid; D013917:Thrombin