A novel cyclized histatin-based peptide DB2-121 that is a potent new antifungal agent active against the clinically important Candida albicans and a number of other organisms.

Key Words: Antimicrobials, Antifungals, Antibacterials, Anti-infectives

Description of the Invention: Histatins are a class of histadine rich peptides, found in human saliva, that exhibit antimicrobial and antifungal properties. This invention, a novel cyclized histatin-based peptide DB2-121, is a potent new antifungal agent active against the clinically important Candida albicans and a number of other organisms. It has been demonstrated to be non-toxic to primary mammalian cells in culture. It was also shown to be most potent against the hyphal form of Candida albicans, which is the life cycle stage where it is most able to infect basal membranes and enter the circulatory system. Toxicological studies proved to be superior to ketoconazole and no acute toxicity was found in mice (15 mg/kg) and human primary neonatal foreskin epithelian cells (5-50 mM) and neonatal foreskin epithelial cells.  

Background: Infectious diseases are a rising health risk to an estimated 9 million patients annually in the 7 major markets worldwide, due in part to the rapid rise of antimicrobial resistant organisms. Patients at risk include anyone who is immuno-compromised due to cancer, surgery, HIV/AIDS, leukemia or organ transplantation. Of the 3.5 million patients hospitalized in the US every year for chemotherapy, AIDS or transplants, one quarter develop fungal infections with mortality rates of 38%

The two classes of drugs currently dominating the market, the azoles and the allyamines are both experiencing increased resistance problems, which limit efficacy and toxicity effects. This is true especially of the azole drugs, which comprise 57% of the worldwide market share, estimated to be worth $4 billion in 2003. This market sector is also experiencing increased pressure from generic drug companies as these established therapeutics come off patent.
As a result there is a growing unmet need for small molecule drugs that are non-toxic to humans and more effective than the endogenous defenses humans possess, or, the toxic azole drugs that are a current standard of care. Fungicides represent the fastest growing segment in the global pharmaceutical anti-infective sector, with the market for antifungal medications and antifungal dermatological agents having grown by 7-8% in the last five years.

Potential Advantages/Uses:

• No cytotoxicity effects to primary human cells in culture
• 500-1000 fold more effective at controlling hyphal growth in C. albicans than ketoconazole
• 100-fold more potent than H5, a naturally occurring Histatin
• Most active at physiological temperatures
• Mechanism of action thought to be unlike other small molecule drugs in this therapeutic
• Significant activity against Bacillus subtilis, a Gram-positive bacteria. 

Reference Number: UWO-AG-012, UWO-AH-043

Preclinical

Issued US Patent 6,555,650 with a priority date of January 1999, CDN patent CA2285673, US provisional filed based on new findings; in vivo mouse underway to test efficacy.

This technology is available for exclusive licensing.  A partnership is also welcome.