Polymedix (www.polymedix. com) creates small molecule mimetics of host defense proteins, eliminating the potential of drug-resistant bacteria as seen with current antibiotics. Exclusively licensed from researchers at the University of Pennsylvania, this process involves several computational design tools.
"The first thing we did was to design a novel antibiotic," says Nicholas Landekic, Ph.D., president and CEO. "Instead of targeting a biochemical molecule, we're disrupting the bacterial cell membrane from the outside. It's difficult to envision how resistance would occur."
The tools include a special force-field, GOLDYN (Global Optimization of Long-Time Dynamics), which takes into consideration solvent effects (i.e., water) on molecular shape and interaction. "Molecular dynamics is a key tool if one is trying to create membrane-active compounds, which is what we're doing with our antibiotic compounds," says Dr. Landekic.
"With the COSMOS (Coarse Grain Molecular Dynamics Simulations) approach, we're able to do molecular dynamic simulations of over several hundred microseconds, even using modest amounts of computer power. This is real-time for the interaction of many molecules with their membrane targets."
PACE (Proteomic-Assisted Computational Engine) is a set of algorithms that build nonpeptide backbones from common organic building blocks. These are built in a variety of shapes to mimic the backbone of the active portion of a protein the company is trying to mimic. Later, functional groups are added to give it biological activity.
The company has tested 300 novel small molecule antibiotic compounds to date and approximately 65% are considered hits. Approximately 50 of the 300 compounds are potent, selective, non-toxic, and considered leads.
"By developing small molecules that mimic host defense proteins, we've achieved compounds that are broad-spectrum, work on a wide range of gram positive and gram negative strains, as well as fungus, and are fast actingbactericidal within seconds to minutes. Most current antibiotics take one to three days to work and only arrest bacterial growth," states Dr. Landekic.
FivePrime Therapeutics (www.fiveprime.com) has developed a platform for the production and screening of all secreted proteins and receptors. The principles of high throughput screening of small molecule compounds are applied to the screening of entire sets of human secreted proteins on primary cells.
The company has the most comprehensive human cDNA collection, with more than 300,000 cDNA, of which more than 90% are full length, with an average of 12 clones per gene.
"Full-length cDNAs give a much better chance to make functional proteins rather than using ESTs, which most companies use," says Ge Wu, Ph.D., director of assay development and screening. These are derived from a tissue bank containing over 2,400 samples from 135 different normal and disease tissues.
High throughput protein production allows for the production of more than 2,000 proteins per week for screening. "Then we put these 2,000 proteins in different assays that are medically relevant. We decide on a disease first, then decide what type of cells are a good target, so we match the cell to the screening. We use primary cells, not cell lines," explains Dr. Wu.
This screening process is automated and has shown results to be reproducible. A database captures activity profiles of all proteins across all screens, which is a key element for lead selection.
The proprietary Espresso in vivo testing system generates information on secreted protein function in animals by mimicking intravenous injection of the protein without the need for protein production.
FivePrime is currently applying this technology to four disease areas: oncology, type 2 diabetes, immune disorders, and regenerative medicine. Dr. Wu says they currently have a "promising target called FPT025, which targets monocytes and T-cells."
A new area is cardiology, where Dr. Wu says the company currently has two projects under way. One is screening for factors that protect the cardiomyocyte after ischemia, and the other is screening for factors that stimulate the regeneration of heart cells from stem cells.