Snake venom phospholipases A(2): a novel tool against bacterial diseases

Curr Med Chem. 2012;19(36):6150-62. doi: 10.2174/092986712804485791.

Abstract

The majority of snake venom phospholipases A(2) (svPLA(2)s) are toxic and induce a wide spectrum of biological effects. They are cysteine-rich proteins that contain 119-134 amino acids and share similar structures and functions. About 50% of the residues are incorporated into α-helices, whereas only 10% are in β-sheets. Fourteen conserved cysteines form a network of seven disulfide bridges that stabilize the tertiary structure. They show a high degree of sequence and structural similarity, and are believed to have a common calcium- dependent catalytic mechanism. Additionally, svPLA(2)s display an array of biological actions that are either dependent or independent of catalysis. The PLA(2)s of mammalian origin also exert potent bactericidal activity by binding to anionic surfaces and enzymatic degradation of phospholipids in the target membranes, preferentially of Gram-positive species. The bactericidal activity against Gram-negatives by svPLA(2) requires a synergistic action with bactericidal/permeability-increasing protein (BPI), but is equally dependent on enzymatic- based membrane degradation. Several hypotheses account for the bactericidal properties of svPLA(2)s, which include "fatal depolarization" of the bacterial membrane, creation of physical holes in the membrane, scrambling of normal distribution of lipids between the bilayer leaflets, and damage of critical intracellular targets after internalization of the peptide. The present review discusses several svPLA(2)s and derived peptides that exhibit strong bactericidal activity. The reports demonstrate that svPLA(2)-derived peptides have the potential to counteract microbial infections. In fact, the C-terminal cationic/hydrophobic segment (residues 115-129) of svPLA(2)s is bactericidal. Thus identification of the bactericidal sites in svPLA(2)s has potential for developing novel antimicrobials.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology*
  • Anti-Infective Agents / therapeutic use
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / metabolism
  • Antimicrobial Cationic Peptides / pharmacology
  • Bacterial Infections / drug therapy
  • Blood Proteins / metabolism
  • Catalytic Domain
  • Cell Membrane / metabolism
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Humans
  • Phospholipases A2 / metabolism
  • Phospholipases A2 / pharmacology*
  • Phospholipases A2 / therapeutic use
  • Snake Venoms / enzymology*

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Blood Proteins
  • Snake Venoms
  • bactericidal permeability increasing protein
  • Phospholipases A2