Biomimetic Drug Design - Imitating Nature

Most experts believe we are losing the war against disease-causing bacteria. About 2.5 million Americans develop serious bacterial infections every year, of which 100,000 die. Bacterial infections are the fourth-leading cause of death in the U.S. Drug developers are scrambling to find solutions to this dire problem.

Nearly every dangerous bacterium today now shows some degree of resistance to antibiotics. Some are “multi-resistant,” meaning almost no drugs will knock them out.

Methicillin-resistant Staphylococcus aureus (MRSA), already common in hospitals, was responsible for only 50 deaths in the U.S. in 1993. In 2002 this bacterium killed more than 800 Americans. At one time MRSA only affected patients with weakened immune systems, but it has recently begun infecting healthy individuals.

The keys to discovering tomorrow’s antibiotics may lie in chemical defenses that have been employed by primitive organisms for millions of years. Molds and other primitive life forms rely almost exclusively on small-molecule defenses, for example penicillin, against bacterial invasion. Mammals possess a more complex first-line immunity. Among the most prominent players in the human immune response are the host defense peptides, or defensins, which rapidly inactivate bacteria before the pathogens can gain a foothold.

Biologists have discovered several classes of defensins, most of which contain between 20 and 40 amino acids. All are amphiphilic, meaning they show affinity for both charged/polar and uncharged/non-polar environments. It is this property that researchers believe to be responsible for host defense peptides’ persistent antimicrobial activity over hundreds of millions of years, despite the evolution of “enemy” bacteria.

The Problem With Protein/Peptide Antimicrobials
Polymedix’s approach to the antibacterial problem is based on biomimetics – very small molecules that mimic the activity of the defensins. Our lead compounds – biomimetic amphiphilic antimicrobial compounds (BAACs) – specifically replicate the activity of host defense proteins.

Some other advantages of BAAC’s compared with existing antibiotics:

• Potent, broad spectrum activity against more than 150 bacteria
• Rapid action that kills bacteria, rather than letting the immune system do most of the work
• Proven activity against drug-resistant bacteria, including MRSA
• Selectivity for bacteria vs. human cells of 100 to greater than 10,000, compared with 10- to 20-fold for host defense proteins;
• Well tolerated in animals
• Ease of manufacture through chemical production methods
• Unlikely to encounter bacterial resistance

Polymedix’s molecular design platform duplicates the structural and biological properties of antimicrobial peptides with easily-synthesized polymers and oligomers. Our computational methods allow us to identify lead compounds in less than 36 months, for less than $10 million.

BAACs are one-tenth the size of naturally-occurring defensins, hundreds of times more powerful at killing bacteria, and a thousand times more selective for bacterial vs. host cells. These molecules are designed to mimic the amphiphilic structure of the host defense proteins – but with completely synthetic, non-peptide backbones.

BAACs cause bacterial cell membranes to rupture, a unique mechanism among antimicrobial compounds. For this reason we believe the molecules will not engender bacterial resistance. Organisms killed by BAACs would need to evolve a new type of cell membrane to evade the killing activity of PMX-10129 and PMX-30016. This is why host defense proteins remain effective despite hundreds of millions of years of bacterial evolution.

Lead Compound Activity
In rodent models of bacterial infection, our lead BAAC compounds show a level of safety and efficacy orders of magnitude more favorable than those of defensins, not to mention many currently marketed antibiotics.

Two of our compounds, PMX-30016 and PMX-10129, are tolerated at doses of up to 45 mg/kg, which is up to 400 times the minimum inhibitory concentration for pathogenic bacteria. These molecules also show up to 1000-fold and greater selectivity for bacteria versus mammalian cells including blood erythrocytes, mouse fibroblasts (3T3 cells), and human liver (HepG2) cells.,

BAACs work by exploiting the unique chemical composition of bacterial cell membranes. Bacteria contain more negatively-charged chemical groups on the outer surface of their membranes than do mammalian cells. Bacterial membranes also lack cholesterol, an essential component of all mammalian membranes. BAACs home in on membranes that lack cholesterol and which contain large numbers of negatively-charged phospholipids – thus, they are specific and selective for bacterial cell membranes, but do not harm animal cells.

Table XX lists the activity of the antimicrobial BAACs, PMX-10129, PMX-30016, against a panel of Gram-positive and Gram-negative bacteria, as well as two anaerobic organisms.

In a rat model of soft tissue infection using Staphylococcus aureus as the infective agent, PMX compounds are more effective than vancomycin in reducing the number of viable bacteria when administered by intravenous injection. I another animal model, of bacterial sepsis, two doses of PMX30006 administered intravenously resulted in full recovery of all infected animals.  All untreated animals died within the first 24 hours after infection.

Versatile Molecular Design Platform
In addition to its anti-infective drug discovery program, Polymedix has employed its molecular design platform towards other therapeutic areas as well as non-clinical products.

Our lead heparin antagonist, PMX-60054, re-establishes normal blood clotting time in a way that is more predictable and convenient than administration of protamine, the most commonly used heparin agonist. Animal studies show that a single administration of PMX-60054 following heparin completely normalizes blood clotting time. Even a significant over-dosage of PMX-60054 causes no apparent deleterious effects on blood clotting time. Significantly, PMX-60054 also works against low molecular weight heparin, thus may be suitable as a universal anticoagulant-reversing agent.

In addition to therapeutic agents, we have identified novel polymeric materials based on BAAC-like structures. These materials hold great promise as self-sterilizing anti-microbial surfaces and bactericidal products. Possible end-use applications include self-sterilizing surface materials, paints and coatings, food and laboratory work surfaces, plastics for food processing and packaging, personal care products, textiles, and some high-value biomaterials applications. Polymedix will most likely out-license anti-microbial materials to bulk polymer or materials formulators.

Conclusion
For the entire history of the pharmaceutical industry, medicinal chemists have turned to nature for products and inspiration. By capturing the salient properties of host defense peptides in a small-molecule format, Polymedix has shown that nature, with a bit of help from computing technology and human ingenuity, is still a rich source of ideas for new therapies. Polymedix is currently planning its clinical development strategy for the anti-infectives PMX-30016 and PMX-10129, as well as our heparin antagonist PMX-60054. We expect to promote compounds from both these programs to Phase I trials by the end of 2007.

Author: Dr. Eric McAllister, PolyMedix