SLE is a systemic, debilitating autoimmune disease with a variety of clinical manifestations affecting multiple organs in the body (64). The Toll-like receptor 7 (TLR-7)/TLR-9/interleukin (IL)-1 receptor-associated kinase 1 (IRAK-1)/interferon regulatory factor 7 (IRF-7) pathway plays a key role in the development and progression of SLE (65-67). Furthermore, it has been observed that PIN1 activity is upregulated upon the activation of TLR7 or TLR9 and interacts with IRAK1 in primary dendritic cells. This interaction is crucial for IRAK1 activation and downstream signaling, including the activation of IRF7 and the induction of type I interferons. Indeed, PIN1 deficiency impairs the nuclear translocation of IRF7, thereby hampering TLR-mediated interferon-dependent immune responses (68). In this context, it has been demonstrated that PIN1 inhibition reduces SLE manifestations and improves overall survival in lupus-prone animal models (69).

In addition, IL-6, a pro-inflammatory cytokine produced by various cell types, has emerged as a crucial regulator in SLE. IL-6 affects the function of different cell types, including T- and B-cells, macrophages and neutrophils by promoting cell activation and differentiation, leading to systemic autoimmunity and subsequent inflammatory responses (70). Multiple studies have revealed elevated IL-6 serum levels in patients with SLE (71). In particular, the IL-6 pathway is suspected to play an essential role in B-cell hyperactivity and immunopathology in human SLE, and may directly mediate tissue damage. Thus, the blockade of IL-6 has been shown to improve the SLE phenotype in various models (72). Actually, IL-6 signaling is driven by the IL-6 receptor and the signal transducer and activator of transcription 3 (STAT3). It has been reported that PIN1 plays a critical role in inducing IL-6 expression in SLE by interacting with STAT3, promoting its phosphorylation at Ser727, and enhancing its transcriptional activity (73) (Fig. 4). Although further research is required to fully elucidate the underlying mechanisms and potential clinical applications, PIN1 inhibition emerges as a promising novel therapeutic strategy for patients with SLE (Fig. 4).

RA is a complex autoimmune disorder characterized by chronic joint inflammation, the destruction of cartilage and bone, abnormal synovial cell proliferation, and the formation of an aggressive tumor-like structure termed pannus (74). Fibroblast-like synoviocyte samples from patients with RA have been observed to exhibit a neoplastic phenotype due to the activation of the NF-κB pathway (75). In addition, NF-κB, a critical player in inflammation and immunity, is pivotal in producing matrix metalloproteinases (MMPs) (76). These enzymes contribute to the destructive nature of RA by participating in cartilage destruction (77,78). Notably, PIN1 has been reported to upregulate NF-κB activity, thereby promoting the tumor-like phenotype of RA synoviocytes. Indeed, an association has been found between the expression of MMPs, NF-κB subunits and PIN1 in the synovial tissue of patients with RA (75).

Moreover, the progression of RA is dictated by inflammatory mediators, such as prostaglandins (PGs) and pro-inflammatory cytokines, that orchestrate the immune response (79,80). Cyclooxygenase 2 (COX2) controls PG production. Notably, in a previous study, both COX2 and PIN1 expression levels were found to be increased in the ankle tissue of mice with RA following induction with type II collagen (81). The overexpression of PIN1 led to the increased expression of COX2. Moreover, it was shown that during the progression of RA, PIN1 induction stimulated the expression of pro-inflammatory proteins, such as iNOS, TNF-α and IL-1β by activating NF-κB, CREB and the C/EBP pathways. Consistently, PIN1 inhibition significantly reduced RA progression and COX2 expression in ankle tissues (81) (Fig. 4). Given the complex interplay of PIN1 and its impact on RA, further research is essential to uncover its potential role as a therapeutic target for the treatment of RA.

IBDs are chronic relapsing disorders encompassing Crohn's disease and UC affecting the colon and small intestine. Symptoms range from chronic diarrhea and abdominal pain to inflammation and epithelial injury involving the gastrointestinal tract. Although the etiology of IBDs remains unknown, it has been proposed that intestinal mucosa damage occurs due to the dysregulated abnormal immune response against the microorganisms of the intestinal flora (82).

Matsunaga et al (83) suggested the contribution of PIN1 to the development and severity of IBDs. Indeed, its expression was shown to be markedly enhanced in the colons of model mice with dextran sodium sulfate (DSS)-induced UC. A PIN1 knockout mouse model consistently exhibited significantly reduced DSS-induced colitis symptoms and colon tissue damage. In the colons of PIN1 knockout mice, its inhibition decreased M1-type macrophages, known for their pro-inflammatory cytokine expression (83). Conversely, M2 macrophages, a producer of anti-inflammatory cytokines, exhibited an increased percentage. Furthermore, PIN1 inhibition was associated with the downregulation of IL-17 and IL-23a expression, cytokines implicated in IBD development (83).

Of note, the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) is exclusively expressed in several inflammatory and autoimmune diseases. This innate immune receptor triggers the inflammasome complex assembly, which has been reported to be associated with various inflammation- and immune-related diseases that are a key factor in the pathogenesis and progression of UC and Crohn's disease. Indeed, the overexpression, aberrant activation, polymorphism and gain-of-function mutation of the NLRP3 inflammasome contribute to IBD pathogenesis (84). Additionally, it has been suggested that PIN1 promotes NLRP3 inflammasome activation through the phosphorylation of the p38 MAPK signaling pathway in macrophages (85) (Fig. 4). A comprehensive understanding of the role of PIN1 in activating NLRP3 necessitates further research on IBDs.

Nonetheless, additional exploration is necessary to unveil its potential as a therapeutic focal point for addressing RA.

HCV is the primary infectious agent of acute and chronic hepatitis, which can eventually lead to permanent liver damage and hepatocellular carcinoma (HCC). HCV, a sheathed RNA virus, has its reproduction reliant primarily on the host cell cycle and requires the involvement of host proteins (88). In particular, PIN1 is a cellular factor required for HCV replication, and it may enhance the viral infection principally due to its interaction with both the NS5A and NS5B HCV proteins. Specifically, PIN1 interacts with the p-Ser/Thr-Pro motifs of NS5A and NS5B, stabilizing them. Notably, Lim et al (89) demonstrated that increased levels of PIN1 were associated with higher levels of intracellular HCV RNA and these viral proteins.

By contrast, when PIN1 is inhibited, it prevents the propagation of HCV by disrupting the interaction between PIN1 and these proteins. Furthermore, NS5B can increase the expression of PIN1, thus promoting its spread (89). Therefore, PIN1 may be exploited as a host target to impair HCV reproduction and infection, emerging as a potential target for antiviral therapies.

HBV is a virus that can lead to chronic hepatitis B, causing cirrhosis, liver failure and HCC. Its genome in the viral capsid is relaxed circular DNA, and when it enters the hepatocyte nucleus, it is converted to covalently closed circular DNA (cccDNA). The transcription of the viral cccDNA is modulated by the HBV-encoded protein, HBx (90). Of note, there is evidence to indicate that PIN1 is overexpressed in HBV-related HCC and that HBx comprises two p-Ser-Pro motifs that can serve as potential targets for PIN1. Actually, PIN1 binds to HBx through its Ser41-Pro motif, enhancing its stability and transactivation, and thereby promoting hepatocarcinogenesis (91,92).

HBx-activated AKT and ERKs also phosphorylate and inactivate glycogen synthase kinase-3β (GSK-3β), leading to the stabilization of β-catenin and cyclin D1 gene transcription, and promoting the development of HCC (93). The overexpression of PIN1 not only elevates the expression of cyclin D1, but also encourages the intracellular buildup of β-catenin in the Wnt/β-catenin signaling pathway. These two signaling pathways can trigger the expression of oncogenes and encourage the occurrence of HCC in HBV infection (94).

In addition, HBV is formed with a core particle composed of multiple HBV core protein (HBc) molecules. Notably, PIN1 has been observed to interact with HBc at the p-Thr160-Pro and p-Ser162-Pro motifs and promote its stability to sustain efficient HBV replication (95). Conversely, Kwon et al (96) recently reported that PIN1 interacts with HBV core particles, but not HBc dimer or monomer. Moreover, they posited PIN1 as a positive regulator of HBV propagation and that the interaction between PIN1 and the core particle may be involved in HBV-associated hepatocarcinogenesis., supported by the observation that PIN1 overexpression enhances, while its knockdown reduces it (96).

EBV, a highly prevalent virus, infects 95% of individuals worldwide at some point. While often asymptomatic, some develop infectious mononucleosis (97). Additionally, an association exists between EBV infection and Burkitt lymphoma and T-cell malignancies (98). Considering the main processes in EBV infection, one of the interesting aspects to analyze is the role of PIN1 in replication. By performing PIN1 knockdown, Narita et al (99) reported that PIN1 promoted viral DNA replication through its interaction with the p-Thr178-Pro motif in the EBV DNA polymerase subunit.

In addition, EBV infection is closely related to nasopharyngeal carcinoma (NPC). The majority of cases of NPC exhibit a distinctive feature: They are nonkeratinizing carcinomas associated with EBV infection (100). In this context, previous studies have demonstrated that PIN1 is overexpressed in all EBV-associated NPC cells, contributing to the growth and aggressiveness of cancer (101,102).

Adult T-cell leukemia/lymphoma is an uncommon malignancy caused by human T-cell lymphotropic virus type I (HTLV-1) (103). The HTLV-1 encodes for an oncoprotein known as Tax and this plays a crucial role in viral gene expression. This protein influences NF-κB signaling pathways, perturbing the normal cell cycle, interfering with apoptosis and prompting genomic instability (104). Tax interacts with a number of human cellular proteins to regulate viral gene expression and foster the pathogenic activation of signaling pathways, such as NF-κB (105). Notably, PIN1 is highly expressed in adult T-cell leukemia cells expressing Tax protein (106). By triggering the E2F/RB pathway, TAX enhances the expression of PIN1. Furthermore, PIN1 binds to Tax when phosphorylated in the p-Ser160-Pro motif in the presence of mitotic kinases (106). Due to PIN1 regulation, phosphorylated Tax interacts with IKKγ to enhance NF-κB activation, promoting cancer progression (107). Furthermore, PIN1 can determine Tax stability by regulating its ubiquitination and lysosomal degradation (106).

HR-HPV can cause cancers of the cervix, vagina, vulva, penis, anus and the back of the throat, including the base of the tongue and tonsils (oropharynx), in both males and females (108). The most frequent type of cancer caused by HR-HPV is cervical cancer, with an annual incidence of >500,000 new cases worldwide (109). Of note, ~14 HR-HPV types are responsible for the majority of cervical cancers, mainly HPV16 and HPV18. The viral protein E2 is a determinant factor that manages viral replication and transcription, and it is employed as an early indicator of HPV infection (110). Notably, HPV-infected cervical lesions exhibit an elevated level of PIN1(44). The increased expression of PIN1 in cervical cancer can enhance the nuclear sequestration of NF-κB (46) and stimulate the transactivation of STAT3, thereby advancing the onset of cancer (48,111). Even a slight, yet significant increase in PIN1 expression has been observed in E2-transfected 293 cells; E2 has been reported to amplify the functionality of PIN1. This evidence suggests that PIN1 activity is addressed by the E2 modulation of the transcription factors, NF-κB and STAT3, driving thus cancer progression (112).

HIV is a lentivirus that targets predominantly CD4⁺ T-lymphocytes and macrophages. Since these T-cells are the regulators of the adaptive immune system, their depletion effectively weakens the immune system, leading to acquired immune deficiency syndrome (AIDS) (113). Several host factors have been shown to play an essential role in the HIV life cycle (114). PIN1 is one of these factors, enhancing HIV infection by being involved in three vital stages of the HIV replication cycle: Cell entry, reverse transcription and host genome integration (115,116). The HIV core depends on PIN1 to discard capsid proteins. PIN1 links to the p-Ser16-Pro17 motif of the HIV capsid protein, reorganizing its structure and removing the capsid from the HIV core (117,118). Furthermore, PIN1 eases the reverse transcription of the HIV genome. The host protein A3G can be packaged into viral particles and induces alterations in DNA during HIV genome reverse transcription. HIV-1 expresses Vif protein to resist the activity of A3G by mediating A3G degradation. Regarding this, PIN1 diminishes A3G expression and prevents A3G from entering HIV particles (87,119). Finally, Saleh et al (116) reported that PIN1 bound to the HIV integrase through its pSer57-Pro motif, thus stabilizing and promoting integrase activity. Consequently, PIN1 improved the insertion of the HIV cDNA into the host genome (116).

The unprecedented outbreak of novel coronavirus disease 2019 (COVID-19) emerged as a worldwide pandemic, causing profound effects on societies across the globe. SARS-CoV-2 is a highly transmissible and pathogenic enveloped, plus-stranded RNA virus with a single-stranded RNA genome (120). Recently, it was established that PIN1 plays a crucial role as a cellular component essential for the propagation of SARS-CoV-2. Yamamotoya et al (121), by using the siRNA-mediated silencing of PIN1 expression, significantly reduced the proliferation of SARS-CoV-2 in VeroE6/TMPRSS2 cells. Several recently developed PIN1 inhibitors exhibited potent suppressive effects on SARS-CoV-2 proliferation, as evidenced by reductions in both viral mRNA and protein synthesis, leading to the mitigation of the cytopathic effect on VeroE6/TMPRSS2 cells (121). Furthermore, Ino et al (122) reported that PIN1 bound precisely to the p-Ser79-Pro motif of the SARS-CoV-2 N protein. However, further in-depth investigations are warranted to elucidate the effects of this interaction on the viral progression. One particular compound, H-77, has demonstrated the ability to block SARS-CoV-2 proliferation with an EC50 <5 µM, regardless of whether it is administered to the culture medium before or following SARS-CoV-2 infection (121). The inhibition of viral N protein mRNA synthesis by H-77 suggests that the underlying molecular mechanism responsible for SARS-CoV-2 suppression likely involves viral gene transcription or earlier stages of infection (121). Another PIN1 inhibitor, all-trans retinoic acid, known to activate the retinoic acid receptor while inhibiting PIN1 activity, also reduced SARS-CoV-2 proliferation. These findings collectively suggest that PIN1 inhibitors are promising therapeutic agents for combatting COVID-19(121).

PD is recognized as the most common neurodegenerative movement disorder. It affects multiple systems, entailing a variety of motor and non-motor symptoms. Pathologically, Lewy bodies (LBs) are the characteristic protein conglomerates in tissues of PD, spanning from the gastrointestinal tract to the neocortex (123). LBs are primarily composed of α-synuclein (124), which is an unstructured protein in its natural state, but can be induced to form an indissoluble α-synuclein cluster in the pathological condition (125). Synphilin-1 is a protein that can interact with α-synuclein, leading to the formation of debris inclusion bodies in the cytoplasm; this interaction plays a central role in creating LBs (126). Due to the absence of a p-Ser/Thr-Pro pattern in α-synuclein, PIN1 does not bind directly to free molecules, but influences α-synuclein through indirect mechanisms (127). When synphilin-1 is phosphorylated, PIN1 can bind through Ser211-Pro and Ser215-Pro patterns, thus indirectly interacting with α-synuclein. The increased expression of PIN1 can impede the degradation of α-synuclein, prolong its half-life, promote its insolubility and contribute to the formation of debris inclusion bodies (128). Hence, it can be speculated that inhibitors targeting PIN1 might alleviate the progression of PD.

AD is a progressive neurodegenerative disorder primarily affecting cognitive functions, particularly memory, thinking and behavior. It is the most common cause of dementia among older adults (129). The disease is characterized by the abnormal accumulation of protein aggregates, including plaques and intracellular neurofibrillary tangles (NFTs). NFTs are clumps of microtubules formed due to the excessive phosphorylation of Tau protein (130). Extracellular plaques mainly consist of aggregates of amyloid-β-peptides resulting from the increased processing of amyloid precursor protein (APP) (131). In the neuronal cells of patients with AD, PIN1 expression is typically downregulated and demonstrates an inverse association with the degeneration of neuronal fibers. In addition, PIN1 facilitates the conformational conversion of GSK-3β-mediated phosphorylated Tau proteins from the dysfunctional cis form to the functional trans form, thus promoting the degradation of Tau proteins (132). Furthermore, PIN1 induces the phosphorylation of APP Thr668-Pro, transitioning it to trans isomer and redirecting APP processing towards non-amyloidogenic pathways (1). PIN1 can directly impede the activation of GSK-3β by binding to the phosphorylated Thr330-Pro motif and catalyzing its isomerization (133). There is evidence to suggest that a decrease in PIN1 expression in the brain generally increases susceptibility to AD and, on the other hand, its overexpression in mature neurons can protect against neurodegeneration caused by Tau hyperphosphorylation (134).

HD is a progressive neurodegenerative disorder characterized by abnormal and repetitive expansions within exon 1 of the gene encoding CAG in the huntingtin protein (HTT), responsible for the degeneration of striatal neurons in the brain (135). The mutated huntingtin protein (mHTT) forms an intranuclear inclusion through misfolding and aggregation (136), which is harmful and it leads to glial proliferation of astrocytes and selective loss of striatal neurons (137). Additionally, it can induce the DNA damage response (DDR) in neurons (138), a significant pathological characteristic of HD. Research has discovered that p53 mediates this cytotoxicity in HD cells and transgenic animal models, and its inhibitors hinder this process (138). Conversely, when PIN1 is silenced, p53 binds to iASPP (a critical inhibitor oncoprotein of p53) regardless of mHTT expression, resulting in the failure to induce apoptosis and consequently preventing mHTT-related neurodegeneration (139). Furthermore, PIN1 is also implicated in DDR and the regulation of DNA double-strand break repair (140).

FTD is a clinical disorder associated with the neurodegeneration of the cortex of the frontal and temporal lobes, often in conjunction with the degeneration of subcortical brain areas. In consequence, behavior, executive function, or language are compromised. FTD is caused by genetic mutations, environmental factors and protein abnormalities (141). Recently, researchers have observed decreases in PIN1 levels across various forms of FTD. These observations have not only been observed in FTD cases with Tau pathology, such as FTD with Tau mutation, Pick disease and cortico-basal degeneration, but also in cases without Tau pathology, such as FTD with motor neuron-type inclusions and neuronal intermediate filament inclusion disease (134).

Additionally, in neurons sourced from the middle frontal gyrus, a shift of PIN1 from the nucleus to the cytoplasm has been identified in all FTD cases, as opposed to typical brains, which conversely exhibit a primary nuclear localization of PIN1(142). Research has demonstrated that the anomalous detected translocation of the mitotic regulator PIN1 depends on the presence of p-Tau, along with the elevated quantity of other target phosphoproteins in neuronal cytoplasm, such as mitotic phospho-epitopes and cell cycle–associated proteins (143). A buildup of these proteins has been noted in diverse pathological contexts (e.g., AD, FTD, parkinsonism linked to chromosome 17, progressive supranuclear palsy and cortico-basal degeneration) and described as signs of the interrupted mitotic process causing cytoskeletal abnormalities and neuronal apoptosis (144). However, additional studies are required to determine whether PIN1 translocation to the cytoplasm represents an early event driving the neurodegenerative processes or if it emerges due to FTD.

ALS is a nerve-deteriorating disease affecting the upper and lower motor neurons, resulting in the paralysis of voluntary muscles, swallowing difficulties, speech impairment and respiratory collapse (145). Recently, Iridoy et al (146) demonstrated a notable downregulation in PIN1 expression in the spinal cord and non-motor cortex of a select group of patients with ALS, signifying PIN1 expression as a potential neurodegeneration indicator. Nonetheless, the existing understanding of the expression profile of PIN1 in ALS is exceedingly limited, as is its role in the pathophysiology of the disease. The literature suggests it may encourage the abnormal piling up of phosphorylated neurofilament proteins in the perikaryon, a significant characteristic of ALS and other nerve-deteriorating diseases. Consistently, PIN1 has been reported to link with phosphorylated neurofilament heavy chain (NF-H) in neurons and to co-locate in ALS-impacted spinal cord neuronal inclusions (147). In rat dorsal root ganglion cultures, exposed to excitotoxic stress to provoke the accumulation of phosphorylated NF-H within the cell body to imitate neurodegeneration, glutamate-induced harm has been shown to heighten phosphorylated NF-H in perikaryal accumulations that co-localized with PIN1 and induce neuronal apoptosis. These effects are mitigated through pharmacological intervention or siRNA-mediated reduction of PIN1 expression, implying that in the face of neurotoxic stress, PIN1 can potentially promote cell death by triggering the assembly of phosphorylated NF-H in the perikaryal (148).

Since the PPI domain is the catalytic domain that provides PIN1 with its isomerase activity, it is not surprising that the vast majority of efforts to find a specific inhibitor of PIN1 have focused on this region of the protein. Below, the developments that were consider most relevant, grouped according to the chemical nature of the inhibitors are described.

The primary strategy used to develop PIN1 inhibitors was based on peptide molecules. In 2005, Bayer et al (151) developed a library of synthetic peptides inhibiting PIN1 using the natural peptide pepticinamin E as the base structure. Thereafter, various developments of PIN1 peptide inhibitors emerged with different rational modifications to improve the binding capacity to this protein and, at the same time, problems caused by the nature of this type of molecule, such as its low-cell permeability and high degradation, highlighting the development of modified cyclic peptides that substantially increase their stability and ability to cross cell membranes. These peptides were shown to exert an anti-proliferative effect in vitro on HeLa cells (152). It should be noted that although the translation of these peptides to PIN1 inhibitor drugs is extremely complex, all these efforts and research provided a large volume of information that allowed for the characterization of different mechanisms to inhibit the PPI domain, which were elegantly reviewed by He et al (153).

As regards the evaluation of small molecules derived from drug design based on the structure of PPI domain inhibitors, in 2009, Pfizer searched PIN1 inhibitors with a massive analysis of more than one million compounds. Although several candidate compounds were obtained, orthogonal assays for biological activity or co-crystallization were not performed (154).

In a recent study, Russo Spena et al (155) searched for PIN1 inhibitors using a library of 35,000 low-molecular-weight compounds through virtual screening based on docking, targeting the PPI domain. This strategy was complemented with molecular dynamics simulations to reduce the number of candidates. Among these, they identified a compound that demonstrated binding to PIN1, and simultaneously, this compound exhibited antiproliferative effects in four different ovarian cancer cell models. It is worth noting that treatments with the candidate compound also reduced signaling pathways associated with PIN1(155).

Covalent inhibitors are a group of chemical compounds that establish permanent bonds with specific proteins, thereby modifying their function and regulation. These inhibitors are highly valued in research and drug development due to their exceptional selectivity and potency. However, they also present challenges in terms of design and the potential for unintended side-effects due to off target nonspecific irreversible binding.

The first PIN1 covalent inhibitor described after the natural compound Juglone was KPT-6566. This inhibitor obtained by mechanism-based screening can selectively inhibit PIN1 and target it for degradation by binding to the PPI domain. This interaction induces cell death in cancer cells in vitro and reduces the growth of lung metastasis in vivo (156).

In a recent study, Liu et al (157) screened using an in-house library of 2,000 electrophilic compounds. Following a series of structural optimizations, they successfully obtained a more potent compound named ZL-Pin13. The covalent binding of this compound with PIN1 was confirmed through crystallography. This compound exerted anti-proliferative effects in breast cancer cell models with IC50 values <3 µM. It also reduced the levels of proteins associated with PIN1, such as Cmyc, Mcl-1 and cyclin D1(157).

The WW domain is essential, granting PIN1 the unique ability to specifically recognize and bind to pSer/Thr-Pro motifs of its target proteins (158). It is important to note that recent research has highlighted the critical importance of the WW site for the proper functioning of the PIN1 protein:

The PIN1 WW domain is phosphorylated on Ser16 both in vitro and in vivo. This phosphorylation regulates the ability of the WW domain to mediate Pin1 substrate interaction. Thus, Ser16 may be critical for regulating WW domain binding activity and Pin1 function (159).

On the other hand, it has been demonstrated that a mutant with the Trp34Ala mutation, which is a highly conserved amino acid in the WW domain of PIN1, experiences a 20-fold reduction in its binding affinity for substrates due to sustained inter-domain contact (160). Consequently, the catalytic pocket remains in a suboptimal conformation and exhibits diminished enzymatic activity (161).

Despite the crucial role of this domain, efforts to develop specific inhibitors targeting WW have been notably limited compared to those directed toward the catalytic PPI domain of PIN1. Nonetheless, it is considered that the flat and shallow interface of the WW domain does not provide a favorable starting point for the rational design of potent PIN1 inhibitors (153).

The most prominent example of an inhibitor designed for the WW domain of PIN1 is a semi-synthetic compound derived from the natural compound, acetyl-11-keto-β-boswellic acid. This inhibitor been shown to exert anti-proliferative and pro-apoptotic effects in prostate cancer cells, underscoring the therapeutic potential of targeting this domain (162).

In this regard, the authors' research team has achieved significant progress by embarking on the first de novo design of inhibitors explicitly tailored to bind to the PIN1 WW domain. The authors previously conducted structural analyses of Trp34 and its vicinity within the WW domain. Through this series of analyses, a novel allosteric region was identified within this domain, constituting a novel pharmacological pocket. By employing a combination of in silico virtual screening based on docking and in vitro biophysical assessments, four small molecules out of 450,000 compounds were successfully identified, that exhibited a high affinity for PIN1(163).

Their distinctiveness compared to other PIN1 inhibitors lies in their exclusive and specific targeting of the WW region, in contrast to other inhibitors that interact with the conserved catalytic PPI domain of PIN1, a feature shared by other peptidyl prolyl isomerases. These efforts represent an essential step in expanding therapeutic options for addressing pathologies associated with the PIN1 protein and highlight the as-yet-unexplored potential of this domain as a therapeutic target.