Elsevier

Drug Discovery Today

Volume 10, Issue 1, 1 January 2005, Pages 23-33
Drug Discovery Today

Review
Lipocalins in drug discovery: From natural ligand-binding proteins to ‘anticalins’

https://doi.org/10.1016/S1359-6446(04)03294-5Get rights and content

Abstract

Lipocalins are a widespread family of small, robust proteins that typically transport or store biological compounds which are either oflow solubility or are chemically sensitive, including vitamins, steroid hormones, odorants and various secondary metabolites. There are approximately ten different lipocalins in the human body, with the plasma retinol-binding protein being the most well known. Some lipocalins have a pathophysiological role, which opens possibilities for their use in medical applications. Furthermore, lipocalins from blood-sucking insects have evolved as scavengers for mediators of inflammation. As well as using the natural ligand-binding function, lipocalins have also been recruited as scaffolds for the design of artificial binding proteins termed ‘anticalins’®. These novel proteins have potential applications as antidotes, antagonistic protein therapeutics or as target-recognition modules in a new generation of immunotoxins.

Section snippets

Pathophysiology of human lipocalins

Ten different lipocalins have thus far been identified in humans: RBP [25], ApoD [15, 16], NGAL [8],α1-microglobulin (protein HC) [26], complement component 8γ [27], tear lipocalin [10, 11], β-trace (prostaglandin D synthase) [28], odorant-binding protein [29], α-1-acid glycoprotein (AGP or AAG) [30] and glycodelin (Gd) [31, 32]. Some of these lipocalins have physiological functions that can be linked to pathological disorders. For example, single point mutations in the RBP gene, which resulted

Insect lipocalins with therapeutic potential

Blood-sucking arthropods have developed several strategies to overcome the mechanisms used by a host to protect itself against invasion. The saliva of most of these insects contains at least one compound that inhibits platelet-aggregation, one substance that interferes with the blood coagulation cascade and one agent that mediates vasodilatory effects [48]. This armament often includes lipocalins, which have evolved sophisticated functions that prove advantageous to the insect [49]. As a

The concept of anticalins as a novel class of therapeutic proteins

Several observations, both on the structural level and from biochemical experiments, support the notion that the β-barrel structural element of the lipocalins represents a rigid folding unit [2]. Despite the varying sequences and diverse binding functions of the natural lipocalins, the backbone conformation of the β-barrel is highly conserved throughout the lipocalins. Hence, this β-barrel structure can support loops with highly variable lengths, sequences and conformations at its open end (

Conclusions and prospects

The lipocalin protein family, either as natural proteins or as artificial ligand-binding proteins with engineered specificities (i.e. anticalins), constitutes a promising novel class of potential biopharmaceuticals. In principle, corresponding protein drugs should have applications in several medical therapies.

References (91)

  • D.R. Flower

    Beyond the superfamily: the lipocalin receptors

    Biochim. Biophys. Acta

    (2000)
  • J. Yang

    An iron delivery pathway mediated by a lipocalin

    Mol. Cell

    (2002)
  • P. Wojnar

    Molecular cloning of a novel lipocalin-1 interacting human cell membrane receptor using phage display

    J. Biol. Chem.

    (2001)
  • B. Åkerström

    Lipocalins: unity in diversity

    Biochim. Biophys. Acta

    (2000)
  • G. Zanotti et al.

    Plasma retinol-binding protein: structure and interactions with retinol, retinoids, and transthyretin

    Vitam. Horm.

    (2004)
  • B. Åkerström

    α1-Microglobulin: a yellow-brown lipocalin

    Biochim. Biophys. Acta

    (2000)
  • Y. Urade et al.

    Biochemical, structural, genetic, physiological, and pathophysiological features of lipocalin-type prostaglandin D synthase

    Biochim. Biophys. Acta

    (2000)
  • T. Fournier

    Alpha-1-acid glycoprotein

    Biochim. Biophys. Acta

    (2000)
  • A. Dell

    Structural analysis of the oligosaccharides derived from glycodelin, a human glycoprotein with potent immunosuppressive and contraceptive activities

    J. Biol. Chem.

    (1995)
  • H. Koistinen

    Glycodelin and beta-lactoglobulin, lipocalins with a high structural similarity, differ in ligand binding properties

    FEBS Lett.

    (1999)
  • H.K. Biesalski

    Biochemical but not clinical vitamin A deficiency results from mutations in the gene for retinol-binding protein

    Am. J. Clin. Nutr.

    (1999)
  • J.F. Kuebler

    Alpha-1-acid-glycoprotein protects against trauma-hemorrhagic shock

    J. Surg. Res.

    (2004)
  • M. Halttunen

    Glycodelin: a reproduction-related lipocalin

    Biochim. Biophys. Acta

    (2000)
  • S. Oehninger

    Factors affecting fertilization: endometrial placental protein 14 reduces the capacity of human spermatozoa to bind to the human zona pellucida

    Fertil. Steril.

    (1995)
  • M. Seppala

    Advances in uterine protein research: reproduction and cancer

    Int. J. Gynaecol. Obstet.

    (2004)
  • E. Yaniv

    Placental protein 14 regulates selective B cell responses

    Cell. Immunol.

    (2003)
  • D. Mukhopadhyay

    Glycodelin A, not glycodelin S, is apoptotically active. Relevance of sialic acid modification

    J. Biol. Chem.

    (2004)
  • J.M. Ribeiro

    Exploring the sialome of the blood-sucking bug Rhodnius prolixus

    Insect Biochem. Mol. Biol.

    (2004)
  • B.J. Mans et al.

    Adaptation of ticks to a blood-feeding environment: evolution from a functional perspective

    Insect Biochem. Mol. Biol.

    (2004)
  • C. Noeske-Jungblut

    Triabin, a highly potent exosite inhibitor of thrombin

    J. Biol. Chem.

    (1995)
  • W.R. Montfort

    Nitrophorins and related antihemostatic lipocalins from Rhodnius prolixus and other blood-sucking arthropods

    Biochim. Biophys. Acta

    (2000)
  • I.M. Francischetti

    Purification, cloning, expression, and mechanism of action of a novel platelet aggregation inhibitor from the salivary gland of the blood-sucking bug, Rhodnius prolixus

    J. Biol. Chem.

    (2000)
  • A. Skerra

    Imitating the humoral immune response

    Curr. Opin. Chem. Biol.

    (2003)
  • R. Huber

    Molecular structure of the bilin binding protein (BBP) from Pieris brassicae after refinement at 2.0 Å resolution

    J. Mol. Biol.

    (1987)
  • A. Skerra

    ‘Anticalins’: a new class of engineered ligand-binding proteins with antibody-like properties

    J. Biotechnol.

    (2001)
  • S. Schlehuber

    A novel type of receptor protein, based on the lipocalin scaffold, with specificity for digoxigenin

    J. Mol. Biol.

    (2000)
  • J.V. Mercader et al.

    Generation of anticalins with specificity for a nonsymmetric phthalic acid ester

    Anal. Biochem.

    (2002)
  • I.P. Korndörfer

    Structural mechanism of specific ligand recognition by a lipocalin tailored for the complexation of digoxigenin

    J. Mol. Biol.

    (2003)
  • M.M. Samama et al.

    Evaluation of the pharmacological properties and clinical results of the synthetic pentasaccharide (fondaparinux)

    Thromb. Res.

    (2003)
  • P.P. Constantinides

    Tocol emulsions for drug solubilization and parenteral delivery

    Adv. Drug Deliv. Rev.

    (2004)
  • H. Schellekens

    Immunogenicity of therapeutic proteins: clinical implications and future prospects

    Clin. Ther.

    (2002)
  • T. Virtanen

    Allergy to lipocalins: a consequence of misguided T-cell recognition of self and nonself?

    Immunol. Today

    (1999)
  • D.R. Flower

    The lipocalin protein family: structure and function

    Biochem. J.

    (1996)
  • D.R. Flower

    Multiple molecular recognition properties of the lipocalin protein family

    J. Mol. Recognit.

    (1995)
  • S.W. Cowan

    Crystallographic refinement of human serum retinol-binding protein at 2 Å resolution

    Proteins

    (1990)
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    lipocalins are promising drug candidates, either based on their natural ligand-binding functions or as engineered ‘anticalins’ with novel specificities.

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    Steffen Schlehuber was born in Fulda, Germany, and studied chemistry at the Technical University of Darmstadt, where he specialized in biochemistry. He went on to complete a doctoral thesis in the laboratory of Arne Skerra at the Technical University of Munich, Germany, obtaining his PhD in 2001. During his doctoral study, Schlehuber was involved in the development of anticalins, which are engineered ligand-binding proteins derived from natural lipocalin proteins. Steffen Schlehuber is cofounder and CSO of PIERIS Proteolab AG, a biotechnology company situated in Freising-Weihenstephan, Germany. Founded in 2001, PIERIS focuses on the development and commercialization of anticalins for therapeutic and diagnostic uses, predominantly in the area of oncology and cardiovascular diseases.

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    Arne Skerra was born in Wiesbaden, Germany, and studied chemistry at the Technical University of Darmstadt. In 1989, he received his PhD at the Ludwig-Maximilians University, Munich, where he had performed, under the supervision of Andres Plückthun and Ernst-Ludwig Winnacker, important research on the bacterial expression of functional antibody fragments. After spending one year as a postdoctoral research fellow with Greg Winter and Cesar Milstein at the MRC Laboratory of Molecular Biology in Cambridge, UK, he joined the department of Hartmut Michel at the Max-Planck-Institute of Biophysics in Frankfurt am Main. In 1994, Skerra became Professor of Protein Chemistry at the Technical University of Darmstadt. Four years later he moved to the Technical University of Munich, where he was appointed a Full Professor to the Chair of Biological Chemistry at the Life Science Campus, Weihenstephan. Skerra is Chairman of the study group on protein engineering and design at the Society for Biochemistry and Molecular Biology and a Board Member of the biochemistry section of the Society of German Chemists. In 2001, he cofounded the biotechnology start-up company PIERIS Proteolab AG.

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