Zonulin Pathway as a Therapeutic Target: Comparison
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The integrity and thus the function of blood–brain barrier (BBB) TJs play a crucial role in the pathomechanism of neuroinflammatory and neurodegenerative diseases. Previously, it has been suggested that targeting different elements of the zonulin pathway, including actin filaments, TJs, or NF-κB, have potential therapeutic effects on CNS diseases. Indeed, encouraging results are accumulating from a recent preclinical study, using myosin light chain kinase (MLCK) inhibitor ML-7, which attenuates BBB disruption by preventing the disintegration of actin cytoskeletal microfilaments. Similarly, blocking the cleavage of TJ proteins by matrix metalloproteases (MMP) inhibitors, using either direct (broad-spectrum or selective MMP-2 and MMP-9) or indirect inhibitors (COX) has been shown to protect BBB. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, such as rosiglitazone, pioglitazone, or D-allose, also prevented BBB integrity by inhibiting NF-κB activation. Therefore, the use of zonulin inhibitors seems to be justified in the treatment of CNS diseases.

  • zonulin
  • zonula occludens 1
  • microbiota
  • gut
  • brain
  • dysbiosis

1. Human Studies with Larazotide Acetate

Over the past decade, larazotide acetate (also known as AT-1001), a pharmacological inhibitor of the zonulin pathway, has received increasing attention. Firstly, Wang et al. published a synthetic oligopeptide (GGVLVQPG) in 2000, representing an N’-terminal sequence of zonulin, which had a strong inhibitory effect on receptor binding of zonulin [1]. Since then, a large amount of knowledge has accumulated on this competitive zonulin inhibitor, demonstrating its strong effect on the regulation of TJs and making it one of the most promising therapeutic candidates for celiac disease [2]. Several interventional human studies have demonstrated good tolerability and beneficial effects of larazotide acetate on intestinal permeability (Table1).
Table 1. Human clinical studies investigating the therapeutic applicability of larazotide acetate.
Condition Results Study

(Enrollment)		 Clinical Trials Identifier Ref.
Healthy good tolerability Phase I

(24)		 NCT00386490 [3]
Celiac disease,

gluten-free diet		 good tolerability Phase Ib

(21)		 NCT00386165 [4]
Celiac disease,


gluten-free diet (terminated based on interim analysis) Phase III

(307)		 NCT03569007 [15][16]
. Viral infections, a role for zonulin has been suggested in the pathomechanism of COVID-19-associated complications. Accordingly, short time proof-of-concept studies in a limited number of enrolled patients have shown that treatment with larazotide acetate improves the clinical manifestations of MIS-C by reducing gastrointestinal symptoms and the severity of systemic inflammation (Table 1) [17][18]. Now, its efficacy is under investigation in a phase II, randomized, double-blind, placebo-controlled clinical trial in patients with MIS-C [19]. In addition, the potential use of larazotide acetate in the treatment of metabolic diseases, including insulin resistance, diabetes mellitus, or non-alcoholic fatty liver disease (NAFLD), as well as to improve glucose and lipid metabolism of patients, has been hypothesized [20].

2. Preclinical Studies with Larazotide Acetate

Recently, human and basic research studies have revealed that high zonulin levels may affect the permeability of not only the intestine but also of other organs. Therefore, numerous preclinical studies have aimed to investigate the efficacy of larazotide acetate in experimental animal models of various diseases. Briefly, treatment with larazotide acetate has been shown to improve epithelial barrier function, thereby attenuating the severity of the investigated disorders, including colitis, vasculitis, fibrosis, arthritis, and respiratory or liver diseases (Table 2).
Table 2. Preclinical animal studies investigating the therapeutic applicability of larazotide acetate.
Model Species Administration Daily Dose Results Ref.
celiac disease gliadin-sensitized HLA-HCD4/DQ8 transgenic mouse p.o.

gavage		 0.25 mg reduced intestinal permeability and macrophage infiltration [21]
p.o.

gavage		 0.3 mg reduced intestinal permeability [22]
Celiac disease, gluten challenge improvement in GI symptoms,
intestinal permeability

good tolerability		 Phase IIa

(80)		 NCT00362856 [ Il10−/− mouse5 p.o.

gavage][6][7][		 5 mg8]
reduced intestinal permeability and inflammation [23] Celiac disease, gluten challenge improvement in histological scores,

good tolerability		 Phase IIb

(105)		 NCT00620451
spontaneous colitis p.o.

in drinking water		[9][10]
0.1 or 1 mg/mL reduced intestinal permeability and inflammation [24] Celiac disease, gluten challenge improvement in GI symptoms, decreased level of anti-tTG IgA Phase IIb

(171)		 NCT00492960 [11][12]
Celiac disease, persistent symptoms with gluten-free diet improvement in GI and extra-GI symptoms,
[41].
Besides larazotide acetate, there is another synthetic zonulin-related peptide fragment known as AT-1002, which, unlike larazotide acetate (AT-1001), has proved to be an agonist of zonulin receptors. Indeed, treatment of epithelial or endothelial cells with AT-1002 led to increased permeability by reversible opening of TJs [42][43]. Since its discovery, AT-1002 has become an important permeability-modulating component in drug development that can be used to increase the absorption and distribution of other drugs [42][44]. Several studies showed that AT-1002 can be used to increase intestinal, intranasal, intratracheal, or transdermal penetration of various compounds improving their bioavailability [45].
These preclinical data suggest that larazotide acetate or other zonulin receptor modulators (by choosing the appropriate route of administration) may prevent BBB integrity and should be investigated in CNS-related diseases, as well.

4. Other Receptor Modulators

Although binding to zonulin receptors, including PAR2 and EGFR, leads to the disruption of TJs, literary data on modulation of PAR2 and EGFR by inhibitors other than larazotide acetate are confusing (Table 3).
Recently, it has been shown that, in contrast to larazotide acetate, peptidic antagonists of PAR2, including FSLLRY-NH2 or SLIGRL-NH2, decreased the expression of ZO-1 and claudin-1 and destroyed the barrier function of nasal epithelial cells [46]. Similarly, a small molecule antagonist, GB83, exerted harmful effects on colon epithelial cells by decreasing the expression of autophagy- and TJ-related factors and increased permeability [47]. In contrast, inhibition of the PAR2 pathway by GB88 in lung epithelial cells [48] or using I-191 in arterial endothelial cells [49] moderated actin rearrangement and TJ disruption and reduced the permeability of the cellular monolayers. Moreover, a non-peptidic PAR2 ligand, the full agonist AC-55541, ameliorated the IL-17-induced loss of epithelial resistance in brain microvascular endothelial cells [50].
The EGFR tyrosine kinase inhibitor AG1478 also prevented TJ disassembly and epithelial resistance impairment in microvascular endothelial cells modeling BBB [51], in lung epithelial-like cells [52], and in oral epithelial tumour cells [53]. In contrast, decreased expression of TJs, barrier dysfunction, and increased permeability were induced by other EGFR tyrosine kinase inhibitors, such as erlotinib [54], gefitinib, icotinib [55], or dacomitinib [56][57] in intestinal epithelial cells. Similar effects were found in other cell types after treatment with lapatinib [58] or vandetanib [59]. These studies suggest that these compounds have a significant impact on the complex signaling pathway of EGFR, triggering stress responses, and finally leading to cell death [55]. This phenomenon may be the underlying molecular mechanism of diarrhea, which is one of the most frequent side effects of second-generation EGFR inhibitors [60].
All these data together suggest that PAR2 or EGFR modulators could be used to regulate epithelial or endothelial barrier function, considering that the applied drug should affect the PPI-DAG-PKC pathway, which plays a central role in zonulin-induced TJ disruption, but not ERK, JNK, or Akt signaling, which are essential for the physiological regulation of basic cellular processes, including cell growth, survival, proliferation, and apoptosis [61].
Table 3. Effect of PAR2 and EGFR modulators on TJ integrity and/or transcellular permeability of epithelial or endothelial cells based on literary data.
Target Type Compound Cell Line Effect on TJs and/or

Transcellular Permeability		 Ref.
PAR2 peptidic antagonist FSLLRY-NH2 pHNECs harmful [46]
SLIGRL-NH2
non-peptidic full agonist AC-55541 hBMECs protective [50]
small molecule antagonist GB88 A549 [48]
DSS induced colitis zonulin transgenic mouse p.o.

in drinking water		 1 mg/mL reduced intestinal permeability [25]


hECs [49] good tolerability Phase IIb

(342)		 NCT01396213 [13][14]
COVID19—MIS-C improvement in clinical symptoms, decreased level of inflammatory markers and SARS-CoV-2 nucleocapsid (N) protein
radiation-induced enteropathy mouse i.p. 0.25 mg improved clinical state and histological scores, inhibited bacterial translocation, elevated TJ protein levels [26]
GB83 Caco2 harmful [47] healthy

(pharmacokinetics)		 pig p.o.

capsule		 0.05 mg/kg
EGFR tyrosine kinase inhibitor AG1478 hCMEC/D3case report

(1)		   [17]
determining pharmacokinetics of larazotide acetate in the small intestine [27]
protective [51] Ruminococcus blautia gnavus colonization germ-free mouse p.o.

in drinking water		 0.15 mg/mL reduced intestinal permeability [28] COVID19—MIS-C improvement in GI symptoms, decreased level of SARS-CoV-2 Spike (S) protein
Calu-3 [52] case series
spontaneous T1D

(4) BB diabetic-prone rat  p.o.

[18]
in drinking water 0.01 mg/mL COVID19—MIS-C (not completed) Phase IIa

(20)		 NCT05022303 [19]
Abbreviations: Ref.: reference; GI: gastrointestinal; MIS-C: Multisystem Inflammatory Syndrome in Children.
As larazotide acetate has successfully passed phase I and II clinical trials, the scientific community has raised the opportunity of its expanded access. As discussed above in the Section 3.2
inhibited development of diabetes
[
29
]
HSC-3
[53]
rheumatoid arthritis mouse p.o.

in drinking water		 0.15 mg/mL attenuated arthritis [30]
erlotinib IEC-6 Il10ra−/− mouse,

Cldn8−/− mouse		 p.o.

gavage		 2 × 0.05 mg reduced intestinal permeability, inflammation, and joint swelling [31]
vasculitis mouse i.p. 0.5 mg reduced intestinal permeability and LPS translocation, prevented cardiovascular lesions [32]
LPS-induced acute lung injury i.t. 0.05 mg reduced severity, decreased inflammatory markers [33]
i.v. 0.01 or 0.025 or 0.05 mg
harmful influenza i.v. 0.15 mg reduced severity of acute lung injury [34]
salivary gland fibrosis i.p. 5 mg/kg improved epithelial barrier function, ameliorated fibrosis [35]
NAFLD p.o.

in drinking water		 0.1 or 1 mg/mL reduced intestinal permeability [36]
p.o.

gavage		 2 × 0.03 or 2 × 0.3 mg
acute liver failure rat p.o.

in drinking water		 0.01 mg/mL decreased intestinal damage [37]
p.o.

gavage		 2 × 0.03 mg
Abbreviations: Ref.: reference; p.o.: per os; i.p.: intraperitoneal; i.v. intravenous; DSS: dextran sulphate sodium; TJ: tight junction; T1D: type 1 diabetes; LPS: lipopolysaccharide; NAFLD: non-alcoholic fatty liver disease.

3. Future Perspectives of Zonulin Antagonists

Larazotide acetate was originally created as an orally administered drug with minimal absorption as the primary target cells were intestinal epithelial cells [2]. The oral administration of a therapeutic peptide can be challenging especially for compounds with expected systemic effect [38]. Systemic drugs have to penetrate the intestinal barriers, including a thick mucus gel and epithelial layer before being digested by luminal enzymes. The phase II clinical trial to evaluate the efficacy and tolerability of larazotide acetate showed that plasma levels were below the quantification limit (0.5 ng/mL) even after 7 or 14 days of daily treatment [5]. Therefore, no systemic effect should be expected after the per os treatment with larazotide acetate. At the same time, as shown in Table 2, summarizing the different methods of administration, intratracheal, intravenous, or intraperitoneal administration of larazotide acetate produced beneficial effects.
The original drug has to undergo further pharmacological development for extraintestinal use. Recent studies have reported that modification of larazotide acetate or its derivates has improved lipophilicity and intestinal absorption [39][40][41]. The resulting compound retained the biological activity of larazotide acetate and was detectable (20–30 ng/mL) in the plasma of mice after a single per os administration
[
54
]
gefitinib
[
55
]
icotinib
dacomitinib T84 [57]
lapatinib HBCCs [58]
vandetanib Calu-6 [59]
Abbreviations: pHNECs: primary human nasal epithelial cells; hBMECs: human brain microvascular endothelial cells; hECS: primary human arterial endothelial cells; hCMEC: primary human cardiac microvascular endothelial cells; HBBCs: primary human breast cancer epithelial cells.

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