Abstract
Over the past few decades advances in modern medicine have resulted in a global increase in the prevalence of fungal infections. Particularly people undergoing organ transplants or cancer treatments with a compromised immune system are at an elevated risk for lethal fungal infections such as invasive candidiasis, aspergillosis, cryptococcosis, etc. The emergence of drug resistance in fungal pathogens poses a serious threat to mankind and it is critical to identify new targets for the development of antifungals. Calcineurin and TOR proteins are conserved across eukaryotes including pathogenic fungi. Two small molecules FK506 and rapamycin bind to FKBP12 immunophilin and the resulting complexes (FK506-FKBP12 and rapamycin-FKBP12) target calcineurin and TOR, respectively in both humans and fungi. However, due to their immunosuppressive nature these drugs in the current form cannot be used as an antifungal. To overcome this, it is important to identify key differences between human and fungal FKBP12, calcineurin, and TOR proteins which will facilitate the development of new small molecules with higher affinity toward fungal components. The current review highlights FK506/rapamycin-FKBP12 interactions with calcineurin/TOR kinase in human and fungi, and development of non-immunosuppressive analogs of FK506, rapamycin, and novel small molecules in inhibition of fungal calcineurin and TOR kinase.
Highlights
Opportunistic invasive fungal pathogens cause significant morbidity and mortality in immunocompromised patients such as those undergoing stem cell or organ transplantation and in individuals with a dysfunctional immune system due to diabetes mellitus or AIDS (Husain et al, 2003; Enoch et al, 2006; Person et al, 2010; Low and Rotstein, 2011; Wang et al, 2017)
All the analogs except 9DP-FK506 exhibited antifungal activity against C. neoformans, A. fumigatus, and C. albicans in vitro, their efficacy was lower when compared to FK506
APX879 exhibits antifungal activity against C. neoformans, C. albicans, A. fumigatus, and M. circinelloides, its efficacy is lower than FK506 in vitro
Summary
Opportunistic invasive fungal pathogens cause significant morbidity and mortality in immunocompromised patients such as those undergoing stem cell or organ transplantation and in individuals with a dysfunctional immune system due to diabetes mellitus or AIDS (Husain et al, 2003; Enoch et al, 2006; Person et al, 2010; Low and Rotstein, 2011; Wang et al, 2017). FK506 exhibits antifungal activity by inhibiting fungal calcineurin (Odom et al, 1997a; Steinbach et al, 2004), but FK506 is an immunosuppressive drug, it cannot be used in its current form to treat patients with fungal infections. Replacing Phe with His (F88H) resulted in a significant increase in resistance to FK506 due to reduced binding of FK506-FKBP12 complex with calcineurin (Juvvadi et al, 2019).
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