FK506/FK520 analogs modified to increase fungal specificity and reduce immunosuppression

Unmet Need

Fungal infections are becoming increasingly prevalent worldwide, with 150 million cases and 1.7 million fatalities reported in the last year alone. The challenge in treating these infections stems from the rise of multi-drug-resistant fungi, which makes conventional antifungal therapies less effective. Moreover, developing antifungals that don’t have significant side effects or cross-reactivity is difficult due to the genetic similarities between humans and fungi. FK506 and FK520 are powerful antifungals that work by inhibiting a fungal protein called calcineurin. Unfortunately, they also inhibit human calcineurin, leading to immune suppression when administered. As a result, FK506 and FK520 are not ideal for managing the rising tide of fungal infections. There is a critical need for antifungal therapies that are highly specific to fungal targets and come with minimal side effects.

Technology

Duke inventors have developed a series of small molecule analogs based on FK506 and FK520 that offer enhanced specificity for fungal calcineurin while minimizing immunosuppressive side effects. This is intended for more effective treatment of fungal infections, without inducing immune suppression, even at high doses. Previous efforts to design fungal-specific calcineurin inhibitors primarily targeted modifications at residue C18. However, recent studies have uncovered the significant role that C21/C22 residues play in calcineurin interactions. Building on this knowledge, Duke researchers synthesized a library of 15 novel C22- or C18-modified analogs of FK506 and FK520. Among these, two compounds—PAD-008 and JH-FK-08—exhibited superior specificity for fungal calcineurin compared to their parent compound, JH-FK-05, an FK506 analog. The enhanced selectivity of these analogs is primarily attributed to modifications at the C22 residue, which effectively prevent cross-reactivity with human calcineurin, thereby avoiding the immunosuppressive effects commonly associated with FK506 and FK520. The antifungal efficacy of JH-FK-08 and PAD-008 has been confirmed through both in vitro and in vivo studies, particularly in mouse models of Cryptococcus neoformans infection.

Other Applications

In addition to their direct antifungal capabilities, these small molecules serve as a foundation for further drug discovery. They can be chemically modified to create additional antifungal compound libraries aimed at developing more potent and selective therapeutics.

Advantages

• Increased specificity to Cryptococcus neoformans calcineurin compared to FK520.
• Reduced immunosuppressive activity compared to FK520.
• Greater efficacy in reducing fungal burden in infected mice versus FK520.
• Ability to be chemically derived into novel compounds, potentially leading to the development of additional antifungal agents.