کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10941020 1095548 2013 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties
ترجمه فارسی عنوان
آنالوگ جدید از مهار کننده بالینی کمپستاتین با خواص سوپنتیومولار و خواص دارویی
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
چکیده انگلیسی
Therapeutic modulation of the complement system has become increasingly important in line with the growing recognition of the role of complement in numerous diseases. Compstatin, a peptidic inhibitor that acts at the central level of the complement cascade, is currently in clinical evaluation but routes to improve its efficacy have not yet been fully explored. Here, we report improvements in both the inhibitory potency and pharmacokinetic parameters of compstatin that broaden its clinical applications. Selective modification of the compstatin N-terminus with non-proteinogenic amino acids resulted in the first analogue with subnanomolar binding affinity (KD = 0.5 nM) and other similarly potent derivatives with improved solubility in clinically relevant solvents. Detailed structure-activity relationship studies based on biophysical and computational methods revealed key structural determinants for the observed improvements. Importantly, pharmacokinetic evaluation in non-human primates revealed target-driven elimination kinetics with plasma half-life values exceeding expectations for peptidic drugs (close to 12 h). This successful optimization strategy is expected to pave the way for systemic administration of compstatin in a range of clinical conditions.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Immunobiology - Volume 218, Issue 4, April 2013, Pages 496-505
نویسندگان
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