Rational combinatorial chemistry-based selection, synthesis and evaluation of an affinity adsorbent for recombinant human clotting factor VII

Morrill, Paul; Gupta, Gautam; Sproule, Kenny; Winzor, Don; Christensen, Jesper; Mollerup, Inger; Lowe, Christopher R.

doi:10.1016/s1570-0232(02)00103-4

Cited by 34 publications

(18 citation statements)

References 21 publications

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“…Synthesis of ligands 6/3 and 6/4 Ligands 6/3 and 6/4 were synthesized in solution following a previously described protocol (Morrill et al, 2002). The first amino substituent was 2-aminoanthracene (6) and the second substituents were 2-amino-3-benzyloxypyridine (3) or 4-amino-1-benzylpiperidine (4).…”

Section: Enzyme-linked Immunosorbent Assay (Elisa) Analysis Of Unbounmentioning

confidence: 99%

“…The first amino substituent was 2-aminoanthracene (6) and the second substituents were 2-amino-3-benzyloxypyridine (3) or 4-amino-1-benzylpiperidine (4). After characterization, the ligands were attached to aminated Sepharose beads with an amine concentration of 11.4 mmol/g gel, following a previously described method (Morrill et al, 2002).…”

Section: Enzyme-linked Immunosorbent Assay (Elisa) Analysis Of Unbounmentioning

confidence: 99%

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The design, synthesis and evaluation of affinity ligands for prion proteins

Renou

Gupta

Young

et al. 2004

J of Molecular Recognition

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Bifunctional affinity ligands based on a triazine scaffold were rationally designed to target prion protein and shown to bind recombinant prion protein with high affinity and selectivity. The ligands were capable of discriminating between prion protein glycoforms and monomeric and dimeric forms of the prion protein. The ligands also discriminate between conformational differences in the prion protein, resulting from point mutations in the prion protein gene. These results suggest that derived compounds could be used selectively to detect the disease-associated form of the prion protein, and as such, could provide diagnostic or therapeutic tools for prion diseases.

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Section: Enzyme-linked Immunosorbent Assay (Elisa) Analysis Of Unbounmentioning

confidence: 99%

Section: Enzyme-linked Immunosorbent Assay (Elisa) Analysis Of Unbounmentioning

confidence: 99%

The design, synthesis and evaluation of affinity ligands for prion proteins

Renou

Gupta

Young

et al. 2004

J of Molecular Recognition

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“…Известно, что при получении фармацевтических препаратов фактора VIII с помощью иммуноаффинных сорбентов нередки случаи возникновения аллергических реакций на остаточный иммуноглобулин мыши [4]. Наилучшей альтернативой традиционным иммунсорбентам являются аффиные сорбенты с иммобилизованными пептидомиметиками [5] или небиологическими малыми молекулами [6]. Такие сорбенты в наименьшей степени подвержены деградации ферментами и не загрязняют продукт иммуногенными биополимерами.…”

Section: Introductionunclassified

Finding small molecule ligand for affinity purification of human coagulation factor VIII by means of the in silico molecular docking

Matskevich¹

2011

Math.Biol.Bioinf.

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Аннотация. При отборе группы синтетических лигандов-кандидатов для очистки рекомбинантного фактора свёртывания крови VIII был использован метод докинга in silico. Созданные Кесслером и соавторами пептидомиметические лиганды L3 и L4, которые обратимо связывают молекулу фактора VIII, были использованы как образцовые лиганды сравнения. Предположительные сайты связывания этих лигандов были размещены на поверхности доменов C1 и/или С2 молекулы фактора VIII. В настоящей работе мы смоделировали взаимодействие лигандов L3 и L4 c предположенными теоретически поверхностями связывания, размещёнными на вершинных областях доменов C1 и C2 фактора VIII. Было обнаружено, что оба образцовых лиганда сравнения связываются с картироваными поверхностями связывания со значительными композитными индексами докинга. Эти поверхности были использованы для докинга библиотек двух поставщиков коммерчески доступных соединений in silico. Конечные композитные индексы докинга наилучших лигандов-кандидатов из обеих библиотек находятся в одном диапазоне, который соответствует образцовым лигандам. Фильтрация исходных библиотек по признаку наличия функциональных групп, за которые лиганды-кандидаты могут быть иммобилизованы на подложку для проверки афинности, специфичности и обратимости связывания, сильно сократило время расчётов при докинге, а добавка (во время подготовки фильтрованной библиотеки к докингу) линкерной группы, за которую лиганд-кандидат мог бы быть иммобилизован на подложку, увеличило химическую релевантность отобранных докингом наилучших лигандов-кандидатов. Группа из малого числа наилучших лигандов-кандидатов будет в дальнейшем проверена на афинность, специфичность и обратимость связывания с фактором VIII.Ключевые слова: докинг, лиганд, фактор VIII, биотехнология. ВВЕДЕНИЕДокинг in silico, или, другими словами, скрининг библиотек химических соединений, является широко распространённым методом поиска новых лекарственных средств [1][2][3]. В настоящей работе мы представляем пример использования обычных программных инструментов скрининга библиотек химических соединений для поиска 1

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“…While small chemical ligands can be used for affinity separations, their utility has traditionally been restricted to cases where they act as a substrate analog, competitive inhibitor, or co-factor for purification of an enzyme. However, recent work with combinatorial libraries has expanded the repertoire for small molecule ligands (Lowe, 2001;Morrill et al, 2002). Often, the strength of this binding interaction is moderate to weak (dissociation constants in the millimolar to micromolar range).…”

Section: Introductionmentioning

confidence: 99%

Development and validation of an affinity chromatography step using a peptide ligand for cGMP production of factor VIII

Kelley¹,

Tannatt²,

Magnusson

et al. 2004

Biotech & Bioengineering

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An affinity chromatography step was developed for purification of recombinant B-Domain Deleted Factor VIII (BDDrFVIII) using a peptide ligand selected from a phage display library. The peptide library had variegated residues, contained both within a disulfide bond-constrained ring and flanking the ring. The peptide ligand binds to BDDrFVIII with a dissociation constant of f1 AM both in free solution and when immobilized on a chromatographic resin. The peptide is chemically synthesized and the affinity resin is produced by coupling the peptide to an agarose matrix preactivated with N-hydroxysuccinimide. Coupling conditions were optimized to give consistent and complete ligand incorporation and validated with a robustness study that tested various combinations of processing limits. The peptide affinity chromatographic operation employs conditions very similar to an immunoaffinity chromatography step currently in use for BDDrFVIII manufacture. The process step provides excellent recovery of BDDrFVIII from a complex feed stream and reduces host cell protein and DNA by 3 -4 logs. Process validation studies established resin reuse over 26 cycles without changes in product recovery or purity. A robustness study using a factorial design was performed and showed that the step was insensitive to small changes in process conditions that represent normal variation in commercial manufacturing. A scaled-down model of the process step was qualified and used for virus removal studies. A validation package addressing the safety of the leached peptide included leaching rate measurements under process conditions, testing of peptide levels in product pools, demonstration of robust removal downstream by spiking studies, end product testing, and toxicological profiling of the ligand. The peptide ligand affinity step was scaled up for cGMP production of BDDrFVIII for clinical trials. B 2004 Wiley Periodicals, Inc.

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Rational combinatorial chemistry-based selection, synthesis and evaluation of an affinity adsorbent for recombinant human clotting factor VII

Cited by 34 publications

References 21 publications

The design, synthesis and evaluation of affinity ligands for prion proteins

The design, synthesis and evaluation of affinity ligands for prion proteins

Finding small molecule ligand for affinity purification of human coagulation factor VIII by means of the in silico molecular docking

Development and validation of an affinity chromatography step using a peptide ligand for cGMP production of factor VIII

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