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Rescher, U. Antifungals for Host-Directed Antiviral Therapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/19992 (accessed on 18 May 2024).
Rescher U. Antifungals for Host-Directed Antiviral Therapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/19992. Accessed May 18, 2024.
Rescher, Ursula. "Antifungals for Host-Directed Antiviral Therapy" Encyclopedia, https://encyclopedia.pub/entry/19992 (accessed May 18, 2024).
Rescher, U. (2022, February 28). Antifungals for Host-Directed Antiviral Therapy. In Encyclopedia. https://encyclopedia.pub/entry/19992
Rescher, Ursula. "Antifungals for Host-Directed Antiviral Therapy." Encyclopedia. Web. 28 February, 2022.
Antifungals for Host-Directed Antiviral Therapy
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This entry is adapted from the peer-reviewed paper 10.3390/ph15020212

Because of their epidemic and pandemic potential, emerging viruses are a major threat to global healthcare systems. While vaccination is in general a straightforward approach to prevent viral infections, immunization can also cause escape mutants that hide from immune cell and antibody detection. Thus, other approaches than immunization are critical for the management and control of viral infections. Viruses are prone to mutations leading to the rapid emergence of resistant strains upon treatment with direct antivirals. In contrast to the direct interference with pathogen components, host-directed therapies aim to target host factors that are essential for the pathogenic replication cycle or to improve the host defense mechanisms, thus circumventing resistance. These relatively new approaches are often based on the repurposing of drugs which are already licensed for the treatment of other unrelated diseases. 

antifungals host-directed drug therapy drug repurposing azoles polyenes echinocandins

1. Polyenes—Disruptors of Fungal Membrane

Polyenes exert their antifungal activity by binding ergosterol in the fungal cell membrane. The resulting membrane disintegration by pore formation increases the permeability, and the membrane leakage leads to the subsequent death of the fungal cell. A well-known, highly effective polyene is amphotericin B, which is widely used in the clinics against invasive fungal infections. Amphotericin B was shown to also induce oxidative stress to fungal cells and modulate the immune system [1].
A potential antiviral capacity of amphotericin B has been reported against a variety of viruses, including human immunodeficiency virus (HIV) [2], Japanese encephalitis virus (JEV) [3], herpes simplex virus (HSV) [4], rubella virus [3] and vesicular stomatitis virus (VSV) [5]. Amphotericin B inhibits the infectivity of JEV in a concentration-dependent manner up to 200-fold at a postinfection step likely at viral replication and/or synthesis of viral proteins without affecting virus adsorption to host cell surfaces [3].
In vitro results highlight the possibility of using amphotericin B against HIV infections, providing a dual effect, against the virus itself and the opportunistic fungal infections that often accompany HIV infections due to the patients’ compromised immune system [2]. Furthermore, amphotericin B potentiated the antiviral efficacy of acyclovir against pseudorabies virus (PRV) without a direct effect on PRV replication in the absence of acyclovir [6]. The mechanism of action remains unclear; however, a recent high-throughput virtual screening approach showed amphotericin B, among other antiparasitic drugs, to possess potential inhibitory features against 10 SARS-CoV-2 molecular targets including the RNA-dependent RNA polymerase [7].

2. Flucytosine—A Selective Inhibitor of Fungal Nuclear Acid Synthesis

Flucytosine as such has no antifungal capacity but is converted by the fungal enzyme cytosine deaminase (which is not present in mammalian cells) into 5-fluorouracil, which is further metabolized. The incorporation of 5-fluorouracil and its metabolites into fungal DNA and RNA then causes aberrant fungal RNA and DNA synthesis [8][9]. 

3. Echinocandins—Noncompetitive Inhibitors of (1,3)-β-D-Glucan Synthase

Echinocandins attack the fungal cell wall by inhibiting the (1,3)-β-D-glucan synthesis and thereby triggering osmotic stress and subsequent cell lysis. They are fungicidal against molds and yeast (most Candida species) and are generally considered well-tolerable due to little adverse effects and drug–drug interactions. Therefore, they are the preferred treatment option for invasive candidiasis [10][11]. Micafungin is an FDA-approved echinocandin that exhibits broad antifungal activity against a variety of Candida species. Of note, a potential antiviral capacity against chikungunya virus (CHIKV) [12], enteroviruses [13] and dengue virus [14], among others, has been reported in recent years. Mosquito-borne CHIKV belongs to the alphaviruses and is a global health problem. Micafungin was able to attenuate the cytopathic effects of CHIKV, reduce viral replication, release and spread, and impair viral stability. Micafungin also had antiviral effects against the alphaviruses Sindbis virus (SINV) and Semliki Forest virus (SFV) [12]. Enterovirus 71 (EV71), the major causative agent of hand-foot-and-mouth disease (HFMD), was shown sensitive to micafungin treatment as well. Micafungin effectively diminished EV71 proliferation and replication already at a micromolar dose [13]. Against other enteroviruses like Coxsackievirus group B type 3 (CVB3) and human rhinovirus (HRV), its antiviral capacity was only moderate. The authors proposed a virion-independent mechanism of action targeting intracellular processes such as translation, polyprotein processing or replication [13]. Recently, micafungin and its analogs, caspofungin and anidulafungin, were suggested for treatment of dengue virus (DENV) infection. In this case, the mechanism of action depends on the direct binding to the envelope protein DENV-2, thereby destabilizing and destroying the virion [14]. Of note, recent in silico studies argued for a binding of the echinocandins micafungin and pneumocandin B0 to the 3C-like protease (3CLpro) of porcine epidemic diarrhea virus (PEDV), as well as to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro), with micafungin having a higher calculated binding affinity towards 3CLpro and pneumocandin B0 binding preferably to Mpro, warranting further investigation into the use of echinocandin-type antifungal drugs as antiviral agents that act via binding to defined viral molecular targets [15].

4. Azoles—Inhibitors of Ergosterol Biosynthesis

The antifungal azoles are classified by the numbers of nitrogen atoms in the azole ring and include imidazoles (e.g., ketoconazole, miconazole, and clotrimazole) and triazoles (e.g., itraconazole, posaconazole, and fluconazole) [16]. Their efficacy and relative safety have led to their widespread clinical use for the antifungal therapy against aspergillosis, candidiasis, and cryptococcosis [17]. While the clinical use of imidazoles (the only exception is ketoconazole) is limited to the treatment of superficial mycoses, triazoles are used for superficial and systemic fungal infections [18]. Azoles exert their antifungal activities through multiple modes of action. By inhibiting the two cytochrome P450 enzymes that function in the ergosterol biosynthesis (CYP51, lanosterol 14α-demethylase) and the conversion of ergostatrienol into ergostatetraenol, (CYP61, 22-desaturase), azoles lead to a depletion of ergosterol. The resulting accumulation of toxic sterol precursors impairs membrane fluidity, asymmetry, and membrane integrity in fungal cells [19].
Interestingly, some of the azoles (itraconazole, posaconazole, voriconazole, and ketoconazole) also impact the mammalian cholesterol metabolism at higher concentrations [20]. Itraconazole and posaconazole influence cellular cholesterol levels by impairing different pivotal steps in the cholesterol homeostasis. Both antifungals include (i) the inhibition of the lanosterol 14α-demethylase and thereby the homeostasis and de novo synthesis of cholesterol [21][22], (ii) the inhibition of the cholesterol-transferring membrane protein Niemann–Pick C1 (NPC1) that results in the accumulation of cholesterol in the endolysosomal system [23], and they further (iii) interact with the oxysterol-binding protein (OSBP), which blocks the shuttling of cholesterol and phosphatidylinositol-4-phosphate (PI4P) between membranes [24]. 

4.1. Itraconazole Directly Interacts with the Endolysosomal Cholesterol Transporter NPC1

Niemann–Pick disease, type C1 (NPC1) protein NPC1 was first identified and characterized as a membrane protein that when mutated causes Niemann–Pick disease, type C1, a rare autosomal neurovisceral lipid storage disorder [25]. NPC1 protein is an endolysosomal integral membrane protein and mediates endolysosomal cholesterol transport [26]. A dysfunctional NPC1 protein, which is found mutated in 95% of the NPC patients, disturbs the intracellular lipid transport, leading to the excessive accumulation of lipid products including cholesterol in the endolysosomal compartment [25]. Interestingly, a possible function of NPC1 as a drug target in antiviral strategies has been explored in several recent publications [27][28]. The Ebola virus entry has been shown to directly rely on NPC1 function via binding of the Ebola virus glycoprotein (GP) to NPC1 [29]. The Ebola virus GP is cleaved by endosomal proteases to unmask the NPC1 binding site, and GP–NPC1 engagement within lysosomes promotes the viral escape into the host cytoplasm [30]. Consistent with this vital dependence of the Ebola virus replication on NPC1 protein, cells lacking NPC1 are nonpermissive for the virus entry and NPC1 knockout mice are protected from lethal Ebola virus infection [29]. Blocking NPC1 has also been reported to cause accumulation of the HIV-1 viral gag protein in the endolysosomal compartment [31][32], resulting in a profound suppression of virion release [32]. The finding that the HIV-1 accessory protein Nef induces host cell genes involved in cholesterol biosynthesis and homeostasis [33] emphasizes the strong dependency of HIV-1 on the host cell cholesterol levels, suggesting that NPC1 is a candidate drug target in the treatment of HIV-1 infections. Interestingly, NPC1 also emerged as a candidate drug target for other enveloped viruses, namely IAV and SARS-CoV-2. Viral replication rates were decreased in cells in which NPC1 was functionally blocked, and the increased endolysosomal cholesterol levels were suggested to interfere with the proper insertion of the fusogenic IAV hemagglutinin domains and the SARS-CoV-2 spike protein, thus affecting virus uncoating [34][35][36].
In many of these and other in vitro studies exploring the importance of NPC1 in diverse cellular functions, the cell-permeable hydrophobic polyamine U18666A, a small-molecule NPC1 inhibitor, was used [37][38]. However, the substantial toxicity of this compound limits a clinical use [39][40]. Of note, itraconazole has been shown to also directly bind and inhibit NPC1 [23], and thus might serve as an attractive candidate for NPC1 targeting strategies via drug repurposing. In favor of this notion, itraconazole-treated cells generated lesser IAV and Ebola virus progeny [36][41], and a beneficial treatment outcome was indeed confirmed in a mouse IAV infection model in vivo [36]. Itraconazole-mediated induction of type I interferons (IFNs), which is considered a fundamental step in establishing antiviral immunity, might also contribute to the observed antiviral effects [36]. While itraconazole also proved its antiviral potential in a 3D cell culture model for SARS-CoV-2 infection [34], an antiviral effect was not seen in the hamster infection model [42].

4.2. Itraconazole Interferes with OSBP and OSBP-Related Proteins (ORP) Functionality

Azoles also impair cellular lipid metabolism via an inhibitory effect on oxysterol-binding protein 1 (OSBP) and on other proteins that belong to the OSBP-related proteins (ORP) family, and this property might add to their antiviral use. OSBP was first identified as an intracellular protein that binds cytosolic 25-hydroxycholesterol [43]. Beside its capacity to bind 25-hydroxycholesterol, OSBP orchestrates the formation of endoplasmic reticulum (ER)–Golgi complex membrane contact sites and thereby shuttles sterols into the Golgi and phosphatidylinositol-4-phosphate (PI4P) back to the ER [44]. OSBP and the family of OSBP-related proteins (ORP) share a lipid-binding domain that binds either a sterol or a nonsterol ligand as well as a PI4P-binding N-terminal pleckstrin homology (PH) domain [45][46]. Another binding motif found in many ORPs, including OSBP, is the FFAT-motif which interacts with the ER-resident VAMP-associated proteins (VAP) receptors [45][46]. Both motifs are involved in shaping the ER–Golgi or, in the case of some viruses, the ER–replication organelle (RO) contact sites and are considerably engaged in lipid transport through different organelles.
Enterovirus, dengue virus, and hepatitis C virus replication are reported to depend on ORP and OSBP [47][24]. Pharmacologic inhibition, siRNA knockdown, and rescue of replication by overexpression have demonstrated the importance of ORPs and OSBP for enterovirus replication and propagation [24]. The virus-induced accumulation of PI4P lipids drives the recruitment of OSBP to these contact sides, and the OSBP-mediated transport of cholesterol and PI4P is pivotal for the formation and functionality of the enterovirus RO [24][48][49][50]. In line, OSBP knockdown and treatment with 25-hydroxycholesterol, an inhibitor of the cholesterol-PI4P exchange, negatively affects virus replication [51]; however, the precise molecular mechanism remains unclear. Itraconazole directly binds OSBP [24], leading to increased PI4P levels at the Golgi (in uninfected cells) or the RO (in infected cells), while the accumulation of cholesterol at the RO is blocked [24].

4.3. Targeting mTOR Signaling via Itraconazole

Itraconazole not only impairs lipid homeostasis, but also affects different signaling pathways, including mammalian target of rapamycin (mTOR), hedgehog, and Wnt signaling pathways that are hijacked by a broad range of viruses to drive the production of infectious particles.
The mammalian target of rapamycin (mTOR) signaling cascade is a pivotal signaling pathway that regulates apoptosis and counteracts stress-induced autophagy (such as, e.g., that elicited by viruses). Although different cellular locations for mTOR complex 1 (mTORC1) and mTORC2 have been reported, mTORC1 lysosomal localization appears critical for its ability to sense and respond to cell starvation [52]. Cholesterol was recently identified to promote the recruitment of mTORC1 to the lysosomal membrane [53] and the mTOR signaling cascade is regulated in a cholesterol-dependent manner [54].
Several viruses have evolved strategies to subvert the mTORC1 signaling network to drive their replication and propagation [55][56][57][58][59][60][61][62][63]. The Semliki Forest virus (SFV), Sindbis virus (SINV), and Chikungunya virus (CHIKV), members of the alphavirus family, cause different diseases but have in common that they encode nonstructural proteins (nsP) [64]. The activation of the PI3K/Akt/mTOR pathway is mediated through the phosphorylated and membrane-attached protein nsP3, which forms the viral replication complex upon virus internalization [65][66][67]. The activation of mTOR signaling is also fundamental for infection with the Flaviviridae West Nile virus (WNV), Japanese encephalitis virus (JEV) and dengue virus (DENV) [68][69][70]. Flaviviridae infection increases mTOR activity through a PI3K-dependent mechanism to maintain translation of its positive-sense RNA genome and also delays WNV-induced apoptosis [58][71][72]. The hepatitis C virus, another Flaviviridae member, increases phosphorylation of mTOR through the nonstructural protein 5A (NS5A) [73]. NS5A seems to activate PI3K/Akt signaling by directly binding PI3K [74][75]. The activation of the mTORC1 pathway by HCV has been linked to antiapoptotic signals that ensure cell survival and maintain persistence by promoting steady-state levels of virus replication [76][77]. Among the β-herpesvirus, the human cytomegalovirus (HCMV) maintains mTORC1 activation [78][79] through the expression of the two HCMV immediate early proteins, IEP72 and IEP86 [80]. Another persistent virus that tightly regulates mTOR signaling pathways is the human immunodeficiency virus type 1 (HIV-1). In dendritic cells, the HIV-1 envelope glycoprotein activates mTOR to prevent autophagy and to increase virus infection. Pharmacological treatment with rapamycin decreased viral spreading [81]. Another study implied that the HIV-1 protein Nef initiates mTOR activation which can be blocked by inhibitors of mTOR or PI3K [82][83], suggesting that drugs that modify the mTORC1 signaling pathway could act as anti-HIV-1 agents [84][85].
Well-balanced mTOR signaling is vitally important for IAV infection [86][87]. Thus, the pharmacological inhibition of the mTOR signaling axis might serve as potential antiviral target. In contrast to other azoles, itraconazole additionally inhibits mTOR signaling through affecting the upstream 5′-AMP-dependent protein kinase (AMPK) [88], which is activated upon an increased AMP/ATP ratio and serves as a regulator of cellular energy levels [89]. Once activated, AMPK inhibits mTOR signaling [90]. The activation of AMPK through itraconazole is a result of direct binding and inhibition of the mitochondrial Voltage-Dependent Anion Channel 1 (VDAC1), a critical regulator of mitochondrial metabolism, resulting in a drop in cellular energy levels [91]. Itraconazole treatment also impairs vascular endothelial growth factor receptor 2 (VEGFR2) functionality in endothelial cells, which is mostly due to altered VEGFR2 glycosylation, trafficking, and signaling [92]. As some viruses like human papillomaviruses or hepatitis viruses promote angiogenesis to facilitate optimal supply by nutrients [93][94][95], this might be an additional beneficial effect of itraconazole in antiviral strategy.

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Ursula Rescher
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