Novel antimicrobial peptides derived from human immunodeficiency virus type 1 and other lentivirus transmembrane proteins

Abstract

We have previously described a conserved set of peptides derived from lentiviral envelope transmembrane proteins that are similar to the natural antimicrobial peptides cecropins and magainins in overall structure but bear no sequence homology to them or other members of their class. We describe here an evaluation of the antimicrobial properties of these virally derived peptides, designated lentivirus lytic peptides (LLPs). The results of this study demonstrate that they are potent and selective antibacterial peptides: the prototype sequence, LLP1, is bactericidal to both gram-positive and gram-negative organisms at micromolar concentrations in 10 mM phosphate buffer. Furthermore, LLP1 kills bacteria quite rapidly, causing a 1,000-fold reduction in viable organisms within 50 s. Peptides corresponding to sequences from three lentivirus envelope proteins were synthesized and characterized. Several of these peptides are selective, killing bacteria at concentrations 50- to 100-fold lower than those required to lyse erythrocytes. Development of antimicrobial agents based on these peptides may lead to improved therapeutics for the management of a variety of infectious diseases.

“Specificity Determinants” Improve Therapeutic Indices of Two Antimicrobial Peptides Piscidin 1 and Dermaseptin S4 Against the Gram-negative Pathogens Acinetobacter baumannii and Pseudomonas aeruginosa

“…Many variations of this assay exist and inconsistency in red blood cells source, peptide exposure time and reporting of peptide concentrations impede comparison of AMP toxicity [57]. The length of time erythrocytes are exposed to AMPs during the hemolysis assay is the least standardized parameter of the method and the most commonly cited times are 30 min [58,59,60] and 1 hour [33,61,62,63]. However, higher exposure times are necessary to evaluate longer-term toxicity.…”

Rational Design of α‐Helical Antimicrobial Peptides to Target Gram‐negative Pathogens, Acinetobacter baumannii and Pseudomonas aeruginosa: Utilization of Charge, ‘Specificity Determinants,’ Total Hydrophobicity, Hydrophobe Type and Location as Design Parameters to Improve the Therapeutic Ratio

“…Reported protocols have exposures ranging from 10 min (28) to 24 h (28,29). The most commonly cited times are 30 min (30–32) and 1 h (33–35). Such short exposures provide valuable information about relative acute toxicity across a peptide series.…”

Antibacterial activity of peptides derived from envelope glycoproteins of HIV‐1

“…The other two domains of gp41 that were appreciably antimicrobial include the N‐terminal heptad repeat region (Fig. 4), which encompasses a portion of the defensin‐like domain [18], and the C‐terminal tail from which LLPs were derived [20–22]. Synthetic peptides corresponding to either the N‐terminal (e.g.…”

“…Since defensins and certain regions of HIV‐1 gp41 share similar characteristics, including size, structure, and cationic charge at neutral pH [18], we have chosen to study whether peptides derived from the HIV‐1 MN envelope glycoproteins, gp120 and gp41, contain defensin‐like antimicrobial activity. Precedents for these studies include several elegant reports revealing a structural correlation between peptides from viral transmembrane proteins and magainins, naturally occurring amphipathic α‐helical antimicrobial peptides from frogs [20–22]. Peptides derived from the C‐terminal region of gp41, termed lentiviral lytic peptides (LLPs), are amphipathic and cationic, and microbicidal against a broad spectrum of bacteria.…”