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Stabilization of proteins by low molecular weight multi-ions

Published on Oct 1, 2002in Journal of Pharmaceutical Sciences3.20
· DOI :10.1002/jps.10219
Donald S. Maclean3
Estimated H-index: 3
(KU: University of Kansas),
Quansheng Qian1
Estimated H-index: 1
(KU: University of Kansas),
C. Russell Middaugh50
Estimated H-index: 50
(KU: University of Kansas)
Abstract
Abstract A method is described to identify small molecule ligands that stabilize proteins. The procedure is based on the hypothesis that molecules of various sizes containing two to four charges should occasionally bind to unpaired charged sites on the surface of proteins and by crosslinking such residues stabilize the native state of the liganded protein. A simple turbidity assay is employed that detects inhibition of protein aggregation under selected sets of conditions. Eight test proteins were screened and in all cases specific ligands were identified that inhibited protein aggregation at millimolar to micromolar concentrations. Only small effects of these stabilizers on protein biological activities were found. In some, but not all cases, circular dichroism and fluorescence studies provided direct evidence of the binding of stabilizing ligands to the proteins suggesting multiple mechanisms of stabilization. This approach should be applicable to the development of excipients for the stabilization of pharmaceutical proteins and industrial enzymes as well as serve as starting points for second‐generation inhibitors of increased affinity and specificity. © 2002 Wiley‐Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:2220–2229, 2002
  • References (23)
  • Citations (50)
References23
Newest
#1Andreas Martin (University of Bayreuth)H-Index: 26
#2Volker Sieber (University of Bayreuth)H-Index: 24
Last.Franz X. Schmid (University of Bayreuth)H-Index: 61
view all 3 authors...
#1Fabrizio Chiti (UniFI: University of Florence)H-Index: 52
#2Niccolò Taddei (UniFI: University of Florence)H-Index: 37
Last.Giampietro Ramponi (UniFI: University of Florence)H-Index: 50
view all 5 authors...
#1Christian Cambillau (CNRS: Centre national de la recherche scientifique)H-Index: 71
#2Jean-Michel Claverie (CNRS: Centre national de la recherche scientifique)H-Index: 70
#1Kazufumi Takano (Osaka University)H-Index: 35
#2Kimiko Tsuchimori (Osaka University)H-Index: 2
Last.Katsuhide Yutani (Osaka University)H-Index: 37
view all 4 authors...
Cited By50
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#1Whitney N. Souery (A&M: Texas A&M University)H-Index: 1
#2Shreedevi Arun Kumar (A&M: Texas A&M University)H-Index: 1
Last.Corey J. Bishop (A&M: Texas A&M University)H-Index: 12
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#1Bing Hu (HBUT: Hubei University of Technology)H-Index: 2
#2Lingyu Han (HBUT: Hubei University of Technology)H-Index: 1
Last.Yapeng Fang (HBUT: Hubei University of Technology)H-Index: 23
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#1Mehri Mortazavi (Pasteur Institute of Iran)H-Index: 3
#2Mohammad Ali Shokrgozar (Pasteur Institute of Iran)H-Index: 39
Last.Elnaz Shams (Pasteur Institute of Iran)H-Index: 2
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