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Improved molecular ...
Improved molecular recognition of Carbonic Anhydrase IX by polypeptide conjugation to acetazolamide
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- Yang, Jie (författare)
- Uppsala universitet,Uppsala University,Organisk kemi
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- Koruza, Katarina (författare)
- Lund University,Lunds universitet,Molekylär cellbiologi,Biologiska institutionen,Naturvetenskapliga fakulteten,Molecular Cell Biology,Department of Biology,Faculty of Science
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- Fisher, Zoë (författare)
- Lund University,Lunds universitet,Molekylär cellbiologi,Biologiska institutionen,Naturvetenskapliga fakulteten,European Spallation Source ESS AB,Stiftelser och övriga anknutna verksamheter,Molecular Cell Biology,Department of Biology,Faculty of Science,Other Institutions and Utilities
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- Knecht, Wolfgang (författare)
- Lund University,Lunds universitet,Molekylär cellbiologi,Biologiska institutionen,Naturvetenskapliga fakulteten,Molecular Cell Biology,Department of Biology,Faculty of Science
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- Baltzer, Lars, 1951- (författare)
- Uppsala universitet,Uppsala University,Organisk kemi
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(creator_code:org_t)
- Elsevier BV, 2017
- 2017
- Engelska.
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Ingår i: Bioorganic and Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 25:20, s. 5838-5848
- Relaterad länk:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- The small molecule inhibitor acetazolamide (AZM) was conjugated to a set of designed polypeptides and the resulting conjugates were evaluated for their affinity to Human Carbonic Anhydrase II (HCA II) using surface plasmon resonance. The dissociation constant of the AZM-HCA II complex was 38. nM and that of the AZM conjugated polypeptide (4-C10L17-AZM) to HCA II was found to be 4. nM, an affinity enhancement of a factor of 10 due to polypeptide conjugation. For Human Carbonic Anhydrase IX (HCA IX) the dissociation constant of AZM was 3. nM, whereas that of the 4-C10L17-AZM conjugate was 90. pM, a 33-fold affinity enhancement. This dramatic affinity increase due to polypeptide conjugation was achieved for a small molecule ligand with an already high affinity to the target protein. This supports the concept that enhancements due to polypeptide conjugation are not limited to small molecule ligands that bind proteins in the mM to μM range but may be used also for nM ligands to provide recognition elements with dissociation constants in the pM range. Evaluations of two HCA IX constructs that do not carry the proteoglycan (PG) domain did not show significant affinity differences between AZM and the polypeptide conjugate, providing evidence that the improved binding of 4-C10L17-AZM to HCA IX emanated from interactions between the polypeptide segment and the PG domain found only in one carbonic anhydrase, HCA IX.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
Nyckelord
- Acetazolamide
- Human Carbonic Anhydrase
- Recognition
- Surface plasmon resonance
- Tumor
- Human Carbonic Anhydrase
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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