Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency

Hongchang Qu; Paola Magotti; Daniel Ricklin; Emilia L. Wu; Ioannis Kourtzelis; You Qiang Wu; Yiannis N. Kaznessis; John D. Lambris

doi:10.1016/j.molimm.2010.10.004

Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency

Hongchang Qu
, Paola Magotti
, Daniel Ricklin
, Emilia L. Wu
, Ioannis Kourtzelis
, You Qiang Wu
, Yiannis N. Kaznessis
, John D. Lambris

Chemical Engineering and Materials Science

Research output: Contribution to journal › Article › peer-review

62 Scopus citations

Abstract

Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH₂) displayed a 1000-fold increase in both potency (IC₅₀=62nM) and binding affinity for C3b (K_D=2.3nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues.

Original language	English (US)
Pages (from-to)	481-489
Number of pages	9
Journal	Molecular Immunology
Volume	48
Issue number	4
DOIs	https://doi.org/10.1016/j.molimm.2010.10.004
State	Published - Jan 2011

Bibliographical note

Funding Information:
We thank Deborah McClellan for editorial assistance, and Paul N. Barlow and Mateusz Maciejewski for their valuable input during discussion of the study. This work was supported by National Institutes of Health Grants GM-069736 , GM-62134 , AI-30040 , EB003968 , CA112162 , and AI-068730 .

Keywords

Complement inhibitor
Compstatin
Isothermal titration calorimetry
N-methylation
Peptide therapeutic
Surface plasmon resonance

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molimm.2010.10.004

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title = "Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency",

abstract = "Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH2) displayed a 1000-fold increase in both potency (IC50=62nM) and binding affinity for C3b (KD=2.3nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues.",

keywords = "Complement inhibitor, Compstatin, Isothermal titration calorimetry, N-methylation, Peptide therapeutic, Surface plasmon resonance",

author = "Hongchang Qu and Paola Magotti and Daniel Ricklin and Wu, \{Emilia L.\} and Ioannis Kourtzelis and Wu, \{You Qiang\} and Kaznessis, \{Yiannis N.\} and Lambris, \{John D.\}",

note = "Funding Information: We thank Deborah McClellan for editorial assistance, and Paul N. Barlow and Mateusz Maciejewski for their valuable input during discussion of the study. This work was supported by National Institutes of Health Grants GM-069736 , GM-62134 , AI-30040 , EB003968 , CA112162 , and AI-068730 . ",

year = "2011",

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doi = "10.1016/j.molimm.2010.10.004",

language = "English (US)",

volume = "48",

pages = "481--489",

journal = "Molecular Immunology",

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publisher = "Elsevier Ltd",

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AU - Qu, Hongchang

AU - Magotti, Paola

AU - Ricklin, Daniel

AU - Wu, Emilia L.

AU - Kourtzelis, Ioannis

AU - Wu, You Qiang

AU - Kaznessis, Yiannis N.

AU - Lambris, John D.

N1 - Funding Information: We thank Deborah McClellan for editorial assistance, and Paul N. Barlow and Mateusz Maciejewski for their valuable input during discussion of the study. This work was supported by National Institutes of Health Grants GM-069736 , GM-62134 , AI-30040 , EB003968 , CA112162 , and AI-068730 .

PY - 2011/1

Y1 - 2011/1

N2 - Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH2) displayed a 1000-fold increase in both potency (IC50=62nM) and binding affinity for C3b (KD=2.3nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues.

AB - Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH2) displayed a 1000-fold increase in both potency (IC50=62nM) and binding affinity for C3b (KD=2.3nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues.

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KW - Compstatin

KW - Isothermal titration calorimetry

KW - N-methylation

KW - Peptide therapeutic

KW - Surface plasmon resonance

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ER -

Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency

Abstract

Bibliographical note

Keywords

UN SDGs

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