Design, synthesis, and in vitro activity of peptidomimetic inhibitors of myeloid differentiation factor 88.
We describe the design and synthesis of a peptidomimetic library derived from the heptapeptide Ac-RDVLPGT-NH 2, belonging to the Toll/IL-1 receptor (TIR) domain of the adaptor protein MyD88 and effective in inhibiting its homodimerization. The ability of the peptidomimetics to inhibit protein-protein interaction was assessed by yeast 2-hybrid assay and further validated in a mammalian cell system by evaluating the inhibition of NF-kappaB activation, a transcription factor downstream of MyD88 signaling pathway that allows production of essential effector molecules for immune and inflammatory responses.
Fantò
Nicola
N
Sigma-Tau Industrie, Pomezia, Italy. nicola.fanto@sigma-tau.it
Gallo
Grazia
G
Ciacci
Andrea
A
Semproni
Mauro
M
Vignola
Davide
D
Quaglia
Marco
M
Bombardi
Valentina
V
Mastroianni
Domenico
D
Zibella
M Pia
MP
Basile
Giancarlo
G
Sassano
Marica
M
Ruggiero
Vito
V
De Santis
Rita
R
Carminati
Paolo
P
D002460:Cell Line; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051193:Toll-Like Receptors / Q000737:chemistry / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009842:Oligopeptides; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors