Database-Guided Discovery of Potent Peptides to Combat HIV-1 or Superbugs

Abstract

Antimicrobial peptides (AMPs), small host defense proteins, are indispensable for the protection of multicellular organisms such as plants and animals from infection. The number of AMPs discovered per year increased steadily since the 1980s. Over 2,000 natural AMPs from bacteria, protozoa, fungi, plants, and animals have been registered into the antimicrobial peptide database (APD). The majority of these AMPs (>86%) possess 11–50 amino acids with a net charge from 0 to +7 and hydrophobic percentages between 31–70%. This article summarizes peptide discovery on the basis of the APD. The major methods are the linguistic model, database screening, de novo design, and template-based design. Using these methods, we identified various potent peptides against human immunodeficiency virus type 1 (HIV-1) or methicillin-resistant Staphylococcus aureus (MRSA). While the stepwise designed anti-HIV peptide is disulfide-linked and rich in arginines, the ab initio designed anti-MRSA peptide is linear and rich in leucines. Thus, there are different requirements for antiviral and antibacterial peptides, which could kill pathogens via different molecular targets. The biased amino acid composition in the database-designed peptides, or natural peptides such as θ-defensins, requires the use of the improved two-dimensional NMR method for structural determination to avoid the publication of misleading structure and dynamics. In the case of human cathelicidin LL-37, structural determination requires 3D NMR techniques. The high-quality structure of LL-37 provides a solid basis for understanding its interactions with membranes of bacteria and other pathogens. In conclusion, the APD database is a comprehensive platform for storing, classifying, searching, predicting, and designing potent peptides against pathogenic bacteria, viruses, fungi, parasites, and cancer cells.

Improved Methods for Classification, Prediction, and Design of Antimicrobial Peptides

“…Sheep anionic peptide SAAP (sequence: DDDDDD) contains no hydrophobic residues in the sequence, leading to a hydrophobic content of 0%, while gramicidins have the highest hydrophobic content of 93%. Thus, the boundary conditions for peptide hydrophobic contents are defined as $$0\%\le \text{hydrophobic content}<93\%.$$ The peak of this hydrophobic distribution is located between 40-50% [46]. This leads to another set of boundary conditions for our database-based prediction.…”

“…The APD [10, 11] also provides a useful platform for identification of useful antimicrobials to combat difficult-to-kill pathogens such as human immune-deficiency virus (HIV) and methicillin-resistant Staphylococcus aureus (MRSA) [46]. Both database screening and database-guided design have been conducted.…”

Cysteine deleted protegrin-1 (CDP-1): Anti-bacterial activity, outer-membrane disruption and selectivity

“…Due to the bactericidal activity of AMPs toward multiple drug resistant bacteria, AMPs are considered to be promising leads for the new generation of antibiotics [4][5][6][7]. The broad spectrum activity of AMPs stems from their ability to destabilize membrane structures of pathogens [8][9][10][11].…”

Microbial flow cytometry: An ideal tool for prospective antimicrobial drug development

“…The total number of AMPs in antimicrobial peptide database (APD3) have been rapidly expanding, which currently lists 2578 AMPs with defined sequence and activity including 261 bacteriocins from bacteria, 4 AMPs from archaea, 7 from protists, 13 from fungi, 321 from plants and 1972 animal host defense peptides (http://aps.unmc.edu/AP/) [4]. The rapid increase in the number of AMPs in databases makes it a challenging task to categorize and uncover the antimicrobial mechanisms of novel AMPs [5]. In recent years, computational and structural comparative studies have begun to unravel physicochemical and structural determinants required for antimicrobial activity of unknown classes of AMPs [6][7][8][9][10][11].…”