Tài liệu Báo cáo khoa học: Multifunctional host defense peptides: intracellular-targeting

MINIREVIEW

Multifunctional host defense peptides:

intracellular-targeting antimicrobial peptides

Pierre Nicolas

Biogene` se des Signaux Peptidiques, ER3-UPMC, Universite´ Pierre et Marie Curie, Paris, France

Introduction

There has been increasing interest in recent years in

describing the complex, multifunctional role that anti￾microbial peptides play in directly killing microbes,

boosting specific inate immune responses, and exerting

selective immunomodulatory effects on the host [1–4].

Furthermore, many antimicrobial peptides are quite

inactive on normal eukaryotic cells. The basis for this

discrimination appears to be related to the lipid com￾Keywords

antimicrobial peptides; cell-penetrating

peptides; dermaseptin; intracellular target;

membrane translocation

Correspondence

P. Nicolas, Biogene` se des Signaux

Peptidiques (BIOSIPE), ER3-UPMC,

Universite´ Pierre et Marie Curie, Baˆtiment A

– 5e`me e´tage, Case courrier 29, 7 Quai

Saint-Bernard, 75005 Paris, France

Fax: +1 44 27 59 94

Tel: +1 44 27 95 36

E-mail: [email protected]

(Received 1 May 2009, revised 25 July

2009, accepted 29 July 2009)

doi:10.1111/j.1742-4658.2009.07359.x

There is widespread acceptance that cationic antimicrobial peptides, apart

from their membrane-permeabilizing ⁄ disrupting properties, also operate

through interactions with intracellular targets, or disruption of key cellu￾lar processes. Examples of intracellular activity include inhibition of

DNA and protein synthesis, inhibition of chaperone-assisted protein

folding and enzymatic activity, and inhibition of cytoplasmic membrane

septum formation and cell wall synthesis. The purpose of this minireview

is to question some widely held views about intracellular-targeting anti￾microbial peptides. In particular, I focus on the relative contributions of

intracellular targeting and membrane disruption to the overall killing

strategy of antimicrobial peptides, as well as on mechanisms whereby

some peptides are able to translocate spontaneously across the plasma

membrane. Currently, there are no more than three peptides that have

been convincingly demonstrated to enter microbial cells without the

involvement of stereospecific interactions with a receptor⁄ docking mole￾cule and, once in the cell, to interfere with cellular functions. From the

limited data currently available, it seems unlikely that this property,

which is isolated in particular peptide families, is also shared by the hun￾dreds of naturally occurring antimicrobial peptides that differ in length,

amino acid composition, sequence, hydrophobicity, amphipathicity, and

membrane-bound conformation. Microbial cell entry and ⁄ or membrane

damage associated with membrane phase ⁄transient pore or long-lived

transitions could be a feature common to intracellular-targeting antimi￾crobial peptides and mammalian cell-penetrating peptides that have an

overrepresentation of one or two amino acids, i.e. Trp and Pro, His, or

Arg. Differences in membrane lipid composition, as well as differential

lipid recruitment by peptides, may provide a basis for microbial cell kill￾ing on one hand, and mammalian cell passage on the other.

Abbreviations

MIC, minimal inhibitory concentration; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol.

FEBS Journal 276 (2009) 6483–6496 ª 2009 The Author Journal compilation ª 2009 FEBS 6483