Background: In an era of questionable antibiotic stewardship there is a increasing need for new antimicrobials as bacteria and viruses become resistant to commonly used drugs. Peptide mimetics have recently been added to our weaponry for the treatment of infectious diseases and they offer some advantages against resistance.
Methods: We have developed peptide mimetics and dominant negative decoy proteins (dNdP) that can block the replication of specific viruses and bacteria by mapping binding domains of essential protein binding partners for selected targets of Influenza virus (virus replicase PA/PB1, PI3 kinase p85β, and TRIM25), Respiratory Syncytial Virus (RSV) (polymerase Phosphoprotein subunit), Chlamydia trachomatis (type III secretion proteins LcrH1, CopD/B, and Cpn0585) using Pepscan epitope mapping and synthesized peptide mimetic inhibitors (10-20mers). A cell penetrating peptide (11-mer) was conjugated to peptide mimetics and dNdP which were expressed in E. coli or yeast as fusions with either maltose binding protein (MBP) human serum albumin (HSA) as the scaffold.
Results: Peptide mimetics and dNdPs inhibited replication of influenza and RSV when added to MDCK cells 10 minutes prior to infection with virus. These antiviral peptides had ID50 values ranging from 10-20 µM. Anti-chlamydial peptides inhibited chlamydial infection of HeLa cells even when added 6 hours post infection. We have recently genetically engineered probiotics and commensal bacteria to synthesize and secrete antimicrobial proteins and are presently testing these antimicrobials in animal models.
Conclusion: We have developed novel antimicrobials including peptide mimetics and dNdP that inhibit both viruses and bacteria. These proteins have been engineered onto a human serum albumin scaffold to increase half life and allow synthesis in gram quantities using commercially available yeast expression systems. These proteins are presently being tested in animal models and if they demonstrate good pharmacological profiles will be candidates for human phase I trials.