One of the central dogmas of molecular biology is the sequence-structure-function relationship: the primary sequence of amino acids determines the protein’s three-dimensional structure that, in turn, defines its function. In the past couple of decades, such a relationship in the field of structural biology has been questioned by the fact that naturally occurring unstructured proteins that deviate from this dogma are increasingly identified. The so-called Intrinsically Disordered Proteins (IDPs), which do not have well-defined secondary, tertiary and, in specific cases, quaternary structures but still exhibit many important biological processes (Dyson and Wright, 2005; Dunker et al., 2001; Kulkarni et al., 2025), have become hot topics in the “proteins world.” Just like other functional molecules, disordered proteins play key roles in molecular and cellular events such as cellular signal transduction, cell cycle, transcriptional regulation, and translation (Tompa, 2002; Iakoucheva et al., 2002; Mishra et al., 2020). Moreover, a great number of proteins that are not commonly classified as IDPs encompass extensive segments characterized by an intrinsic disorder, often defined as intrinsically disordered regions (IDRs). These IDRs are widely distributed across the proteome of different organisms with significant variations within the entire protein in terms of composition and percentage content (Dunker et al., 2001; Peng et al., 2015).

Despite the fact that disordered regions act as mediators of cell signaling and other indispensable biological processes, generally, their essential role has a biological cost: IDRs, not protected by a structure, are more prone to involvement in mis-functional processes, i.e., aggregation above all.

Physico-chemical changes in the cellular environment can, in principle, affect their normal functions consequently leading to pathogenesis and diseases.

One of the hallmarks of many viruses is the effective utilization of their own IDPs/IDRs to perform essential cellular processes to escape from the host defense mechanism (Davey et al., 2011; Dyson and Wright, 2018). This outlines the importance of a thorough characterization of the role of IDRs to understand the molecular mechanism of diseases beyond the classic structure−function paradigm.

Even though the characterization of IDPs and IDRs is a major challenge in biology, since the outbreak of Coronavirus disease 2019 (COVID-19) tremendous efforts have been made to unravel the structural biology of IDRs in the SARS-CoV-2 proteome. A plethora of computational and experimental spectroscopic techniques such as Nuclear Magnetic Resonance (NMR), Circular Dichroism (CD) and Small-angle scattering of X-rays (SAXS), have been used to study these dancing proteins. Beyond reviewing the common knowledge on IDPs and IDRs, the aim of this review is summarizing and analyzing the intrinsically disordered regions of the SARS-CoV-2 proteome, the information available on their biological role, their interaction with globular domains, their importance as source of mutations and viral transmissibility, and the potential involvement with the host cellular machineries. Firstly, we highlighted the percentage of the intrinsic disordered regions within different proteins across the SARS-CoV-2 proteome and opted to summarize the role of IDRs in Nucleocapsid and Non-structural protein 1. We then discuss the role or association of IDRs with SARS-CoV-2 infectivity and transmissibility along with experimentally and computationally explored molecular driving forces acting as local determinants of IDRs conformational changes. Finally, focusing on the SARS-CoV-2 proteins that contain significant disordered regions, we highlighted the potential involvement of their IDRs in the viral-host protein interactions and the effects on the host cellular machinery.

Coronaviruses (CoVs) are a widely varied family of enveloped positive-sense single-stranded RNA viruses. By virtue of their ubiquitous presence in nature, they are broadly spread among mammals and avian species. CoVs belong to the Coronaviridaes family of the Nidovirales order and can be classified into four genera: alphacoronavirus, betacoronavirus, gammacoronavirus and deltacoronavirus.

Betacoronavirus (β-CoV), such as Severe Acute Respiratory Syndrome Coronaviruses (SARS-CoV-1 and SARS-CoV-2) and Middle Eastern Respiratory Syndrome virus (MERS-CoV), are highly pathogenic viruses for humans that share similar genome and replication strategies (Enjuanes et al., 2006; V’kovski et al., 2021).

The SARS-CoV-2 genome, with an approximate length of 30 kb, encodes structural proteins, non-structural proteins (NSPs), and a number of accessory proteins. The four major structural proteins, namely, Spike (S), Nucleocapsid (N), Membrane (M), and Envelope (E) protein, are essential components required for the production of a structurally complete viral particle. Specific interactions between the viral S protein and host cell surface factors, serine protease TMPRSS2, and the receptor angiotensin-converting enzyme 2 (ACE2) promote viral uptake and cellular fusion. N protein is implicated in RNA encapsidation, while proteins E and M guarantee RNA genome (+ssRNA) incorporation into viral particles during the assembly process.

Upon infection, the incoming viral RNA is uncoated inside the host cytosol and two large viral open reading frames, ORF1a and ORF1b, are translated into two polyproteins, pp1a and pp1ab, that are further cleaved into 11 and 15 Nsps, respectively. The 16 Nsps thus produced form the viral replication and transcription complex (Figure 1) (V’kovski et al., 2021; Masters, 2006; Wang et al., 2017; McBride et al., 2014; Malone et al., 2022).

Bioinformatics studies analyzed the percentage of intrinsic disorder (PID), quantified as the ratio between residues predicted to be disordered and the total number of residues, in the MERS-CoV proteome and in individual proteins derived from the MERS-CoV genome. Predicted percentage of intrinsic disorder (PPID) is a metric calculated as the ratio of disordered residues (those predicted to be disordered) to the total number of residues, expressed as a percentage, which is used to estimate the degree of intrinsic disorder within a protein (Rajagopalan et al., 2011; Redwan et al., 2019). Thus, the levels of PPID were applied to categorize proteins as highly ordered (PPID <10%), moderately disordered (10% ≤ PPID <30%), and highly disordered (PPID ≥30%) (Rajagopalan et al., 2011; Giri et al., 2021). According to these examinations, N proteins are characterized by a higher value of PID (Goh et al., 2020; Goh et al., 2013; Alshehri et al., 2021).

In the scenario of SARS-CoV-2, a significant (refers to the percentage) level of disorder content was found for the S1 subunit of S protein and up to 51% for N protein. In these intrinsically disordered regions an abundance of mutations occurring in the 14 major variants were localized [Variants of Concern (VOC)]: Alpha, Beta, Gamma, Delta, Omicron BA.1 and BA.2; Variants of Interest (VOI) Lambda, Mu, Epsilon, Zeta, Eta, Theta, Iota and Kappa.) that could favor the virus with benefits for genetic and antigenic drift (Anjum et al., 2022; Quaglia et al., 2022). Another study buttresses that N protein possesses a predicted PID value of more than 60% and demonstrates moderate content of disorder for some of the nonstructural proteins and accessory proteins, namely, Nsp8, Nsp1, ORF6, ORF9b (Giri et al., 2021; Anjum et al., 2022; Rezaei et al., 2022). Interestingly, the nonstructural proteins, including Nsp2-Nsp6, Nsp9, Nsp10, and Nsp12-Nsp16 of SARS-CoV-2 proteins, show a quite less content of disordered regions (Giri et al., 2021; Anjum et al., 2022).

Along with interplay between the structured part and the IDRs within each specific protein, the vast majority of disordered regions in the SARS-CoV-2 are also involved in protein-protein interactions with other viral and host proteins. Protein-protein interaction (PPI) is a key biological process, established often in a specific and stable manner by a physical contact of two or more proteins in cells which form a complicated network termed “interactome” (Koh et al., 2012; Venkatesan et al., 2009).

Due to the dynamic nature of proteins, the environment in which they exist largely influences their motion, and it must be taken into proper consideration while discussing protein-protein interactions (PPI) (Figure 5).

IDPs are prone to posttranslational modifications (Darling and Uversky, 2018; Jin and Gräter, 2021; Niklas et al., 2015) and, therefore, are likely to exist as chemically heterogeneous intracellular populations. Compared to the structured proteins, IDPs are more susceptible to environmental changes that can determine the IDR/IDP structure and function. The term “environment” intends a broad context: physicochemical environment (pH, viscosity, pressure, salt concentration, etc.) (Lindsay et al., 2021; Verma et al., 2020), biomolecular environment, (interactors and location), physiological environment (cell-type, cell-cycle, stress, etc.) (Verma et al., 2020), and intramolecular interactions (Bugge et al., 2021; Bugge et al., 2020).

As well documented from physicochemical (Lin et al., 2018) and quantitative studies (Bowman et al., 2020), amino acid sequence encodes IDRs conformational behavior as well as their interaction and function (Das et al., 2015; Chong and Mir, 2021). Collectively, many studies evidence that polypeptides and proteins that carry high net charges are known to undergo extended conformations. Charged residues in intrinsically disordered proteins also drive the interaction with biomolecules (Bowman et al., 2020; Milorey et al., 2021).

Transient interactions are another attribute that characterize disordered proteins. Multiple interactions contribute to their dynamic behavior and to possible structural transitions. In many cases, hydrophobic interactions primarily play a role in the disorder-structure paradigm of the IDR systems. Abyzov et al. showed liquid−liquid phase separation (LLPS) derived as a result of intermolecular interactions. The interaction was observed to be responsible for modulating internal motions, slowing down the time scales of IDP motions, and restricting the amplitude of the local backbone conformational sampling (Abyzov et al., 2022). In their analysis, the authors noted that the locally accessible surface determines the interaction between IDP tails and the folded domains that in turn act as local determinants of IDR conformational behavior. In their study, Taneja and Holehouse exploited this behavior to investigate the role of the relative position and accessibility of charged residues across the surface of a folded domain. Simulations on homologs protein with variable charge distribution demonstrated that even slight changes in surface charge impact IDR behavior and interaction with folded domains (Taneja and Holehouse, 2021). Of note, due to the presence of multiple charge patches on naturally occurring proteins and their physical accessibility to local IDRs, these changes in the chemical environment are highly relevant to modulate the interaction (Wohl et al., 2025).

Mukherjee et al. used conformation-sensitive single-molecule Förster resonance energy transfer and CD to understand the effects of cellular components on the conformation of the SARS-CoV-2 RG-1 RNA G4Q. The authors confirmed that salts, co-solutes, crowders, and other IDPs affect the conformation of the SARS-CoV-2 RG-1 RNA G4Q. For instance, in the absence of monovalent K⁺ salt, the RG-1 SARS-CoV-2 RNA-G4Q exists as an equilibrium between folded and metastable conformation, whereas at a high concentration of K⁺, only the fully folded conformations are preserved. Recent reports of Parkinson’s disease cases involving young patients after SARS-CoV-2 infections showed that amyloidogenic disordered α-Syn-derived peptides stabilized the folded state of RG-1 G4Q, although human islet amyloid polypeptide (hIAPP) stabilized the partially folded state, leading to the conclusion that these interactions may afflict expression profiles of disease-modifying genes (Mukherjee et al., 2022). Yesudhas et al. used molecular dynamics simulations to investigate the binding contributions of intrinsically disordered residues of S protein to human ACE2 proteins. They observed a disorder-to-order transition (DOT) profile upon binding that is strengthened mainly by the hydrophilic and aromatic residues localized in the region that undergoes such disorder-to-order transition. The authors hypothesized that this more energetically favorable binding of receptor binding domains with ACE2 is due to the positively correlated motion of the DOTs with its neighboring residues (Yesudhas et al., 2021; Akbayrak et al., 2022). Moreover, the conformational disorder of the N- and C-terminal residues and water accessibility of the SARS-CoV-2 envelop protein increased in acidic pH and high calcium ions concentration (Medeiros-Silva et al., 2022).

As discussed in the previous sections, the interaction of N-protein with the genomic RNA and other membrane proteins is a vital process for the assembly and release of new virions. To get insights into the evolution of drug resistance mutations, it is imperative to comprehend the mechanisms by which mutations are rectified by the virus. In this part, we summarize the contribution IDRs and IDPs across the SARS-CoV-2 genome in bearing mutations, modulating the protein functions and association with variants of SARS-Cov-2.

Genetic variations across the SARS-CoV-2 genome are associated with the frequency of variants, the transmissibility of the virus, and the anti-viral immune response of the host. Mutations in different proteins govern viral replication efficiency, transmissibility, and virulence properties. In the same scenario, mutations affect the properties of proteins and IDR patterns; they may increase as well the size of the IDRs, all of which have an essential effect on folding and SARS-CoV-2 pathogenesis. As IDRs mediate coronavirus transmission (Goh et al., 2020; Tomaszewski et al., 2020; Podder et al., 2021), offering also sequence and structural flexibility, they are believed critical for immune evasion and antibody escape (Quaglia et al., 2022; Li et al., 2024) through diversification and adaptation within its new host.

Several lines of experimental and computational studies were accomplished soon after the emergence of the pandemic, clearly demonstrating that expansion and frameshift of mutations, including the dominant variants of N and S proteins, mainly emerge across the intrinsic disorder regions in the SARS-CoV-2 proteome. This points out the vital role of IDPs in the emergence of new variants and higher transmissibility than previous SARS‐coronaviruses (Quaglia et al., 2022; Feng et al., 2024; Fang et al., 2021).

The infection of SARS-CoV-2 in humans requires S proteins, which bind to the human ACE2 proteins. Particularly, several disordered regions in the receptor binding domains (RBDs) of Sprotein facilitate the interaction (Yesudhas et al., 2021). Multiple studies observed numerous pairwise interactions within unstructured regions while examining the atomic interaction between SARS-CoV-2 and ACE2 (Bhattacharjee et al., 2021; Celik et al., 2021; Michelitsch and Weissman, 2000; Campbell et al., 2021).

The mode of transmission and rigidity of the coronavirus outer shell appeared to be influenced by the unstructured region of Membrane and Envelope proteins (Goh et al., 2020), confirming the strong association between variants of SARS-CoV-2 and its intrinsically disordered regions (Quaglia et al., 2022; Gomari et al., 2023; Sinha and Roy, 2023; Ye et al., 2021).

From the analysis of 219.909 SARS-CoV-2 N sequences, most mutations localized in the intrinsically disordered regions, particularly in the SR-rich linker region (Zachrdla et al., 2022), that were as such believed to be the culprits in increasing the spread of the SARS-CoV-2 virus (Johnson et al., 2022; Rahman et al., 2021).

At the early stages of the SARS-CoV-2 outbreak, the increased spread of variants, including B.1.617.2 (Delta), which contains the R203M mutation has been noticed. Later on, this mutation (R203M) in N and D614G in S were documented along with the other six mutations (P323L in Nsp12, D614G in S, the T492I in Nsp4, R203M in N, T60A in Orf9b, and P1228L in Nsp3) that had greater than 50% frequency in the global SARS-CoV-2 mutations (Abbasian et al., 2023).

In a general context, the diversity of structural ensembles for proteins and protein-protein complexes can be explained by the major concepts of frustration and fuzziness. As illustrated in Figure 5, researchers used the terms frustration to describe conformational variations in proteins and fuzziness to describe how conformational heterogeneity occurs in protein complexes involving IDRs (Freiberger et al., 2021; Gianni et al., 2021). In this regard, Haque et al. analyzed 228 mutations from each domain of the N protein of the SARS-CoV-2. Accordingly, 11 mutations are predicted to be deleterious and destabilizing. Among these mutations, R32C, R191C, and R203 M mutations are localized in the disordered regions and show a significant change in frustration state (from neutral frustrated to major minimally frustrated state), which could raise the sampling of conformation space (Haque et al., 2023). It is worth noting that the R203M mutation improves RNA packaging mechanism and production of higher titers of infectious virions (Haque et al., 2023; Syed et al., 2021).

Phosphorylation of the SARS-CoV-2 Nucleoprotein recruits human cytosolic 14-3-3 proteins, essential for virus replication. 14-3-3 isoforms have the highest expressed rate in a number of tissues, including the brain, lungs, and gastrointestinal system. A recent study predicts the effect of N mutations on the interaction of N protein with human cytosolic 14-3-3 proteins. The S202R mutation demonstrates the profound effect on the efficiency of N protein to package RNA. R203K/G204R mutations, that occurred in the IDRs, appear to enhance the interaction with the 14-3-3 binding motif due to a predicted Arg204:Asp225 salt bridge (Tugaeva et al., 2023). Moreover, it was observed that the arginine at site 203 decreased in prevalence by 8.33% (from 81.9% to 73.5%) as the incidence of a lysine variant increased by 8.2% (from 18.12% to 26.32%). The glycine residue of the directly adjacent 204 site was exchanged by an arginine, increasing of 8.2% the incidence of the mutation (from 18.1% to 26.3%) (Tomaszewski et al., 2020). These results underscore the importance of these specific mutations in contributing to the function of the disordered SR rich region of the protein. Notably, SR rich region in the IDR2 of the N protein that includes the R203K mutation was the hot spot harboring 7 of the top 10 most frequent mutations (Zhao et al., 2021). Mutant proteins bearing mutations in these regions resulted in noticeably weaker phase separation with respect to the wild-type N protein. As confirmed by deep sequence data analysis of SARS-CoV-2 from public databases and clinical samples, the R203K/G204R variant was also associated with novel transcription-regulating sequence-core sequence-dimerization domain RNA, that is supposed to have an increased effect on the expression of sub-genomic RNA (Leary et al., 2021).

Another important aspect of mutations is their role in modulating the viral-host protein-protein interaction. Interestingly, Del Veliz et al. suggested the presence of compensatory mutations in N disordered regions containing binding motifs for 14-3-3 proteins. From analysis of the variability of about 90, 000 sequences of the SARS-CoV-2 N protein, it has been observed that most residues were highly conserved within the 14-3-3 binding site. Moreover, the compensatory mutations, including half of the variants of concern, were found to maintain the interaction energy of N-14-3-3γ which is suggested to be beneficial for the virus (Del et al., 2021).

Protein-protein interactions are initiated by molecular recognition features (MoRFs) (Mohan et al., 2006; Kotta-Loizou et al., 2013), the abundance of which is highly associated with the amount of intrinsic disorder in different forms of life (Yan et al., 2016). MoRFs are small disordered regions situated within intrinsic disorder proteins or regions that undergo a disorder-to-order structure arrangement during interaction with their partners (Gypas et al., 2013; Mishra et al., 2018).

Short linear motifs often located in intrinsically disordered regions offer a mechanism to hijack a large number of host processes (Van Roey et al., 2013; Van Roey et al., 2012). In SARS-CoV-2, nearly all proteins are predicted to have a significant percentage of MoRFs (Giri et al., 2021) suggesting the role of IDRs in protein-protein interaction networks. It has been observed that the replacement of hydrophobic to polar and charged amino acids in S glycoproteins of SARS‐CoV-2 creates an intrinsically disordered region that facilitates proteolysis and fusion with the host membrane (Podder et al., 2021). The antigenicity of the SARS-CoV-2 is due to the structural flexibility of its surface proteins. In S glycoproteins, mutation‐driven accumulation of intrinsically disordered residues has been noticed and hypothesized to enhance viral transmissibility. This overlap between IDRs and major antigenic sites in the receptor-binding domain and N-terminal domain of S glycoprotein (S1 subunit) (Quaglia et al., 2022) is further implicated in the virus to provide genetic and antigenic drift.

While the mutations that originated in the intrinsically disordered regions improved the viral fitness and affected the interaction with the human proteins, it is possible that they influence protein folding and glycosylation leading to structural modifications. Studies by Fang et al. reported nonsynonymous single nucleotide variants (SNVs) on more than 60% of each S, ORF1ab, and ORF3a, with significantly higher SNV occurrence ratios in IDRs of S and ORF1ab. The authors observed mutations in the IDRs of S located near N‐linked glycan sites, postulating potential impacts on glycosylation and protein folding, as well as on elevated levels of hydrophobicity (in S, ORF1ab, but not in ORF3a) (Fang et al., 2021).

Single mutations can affect the intrinsic disorder predisposition of viral proteins. In their per-residue disorder analysis, Hassan et al. used predisposition scores from 0 to one for the per-residual conditions, where 0 and one indicate residues entirely arranged and completely disordered, respectively. Accordingly, with different degrees of disorder predisposition, they observed that single mutations had a pronounced effect on the intrinsic disorder predisposition of ORF10 at the N- and C- terminal of its regions (Hassan et al., 2022). Mutations that emerge on the intrinsic disordered regions, could also lead to the development of drug and vaccine resistance. For example, as compared to wild type, receptor-binding domain mutants of Omicron, Delta AY.1, AY.2, and AY.3 were determined to be more disordered (Ranjan et al., 2022). This increase in disorder could perturb the interactions with antibodies, thus favoring the virus for antibody escape and, as a consequence leading to more pathogenicity.

It is also possible that mutations at the IDRs may lead to structure destabilization. For example, both SARS-CoV-2 and SARS-CoV-1 deletion and substitution mutations of Nsp1 in the C-terminal motif IDR significantly destabilize the structure of Nsp1 (Rezaei et al., 2022). In fact, point mutations at R99 and residues Arg124-Lys125 near the predicted unstructured regions of Nsp1 also lead to the loss of its ability to recognize viral RNA (Mendez et al., 2021; Lokugamage et al., 2012). Also interestingly, K129E and G130R mutations at the beginning of the intrinsically disordered C-terminal domain strongly reduced the ability of SARS-CoV-2 Nsp1 to inhibit cellular translation (Frolov et al., 2023).

The unusually large genome of coronaviruses provides high structural complexity and intricate molecular interaction to efficiently replicate their genome. Once inside the infected cells, a spatiotemporal-oriented coordination between a cohort of enzymes, supporting proteins, and the host multiple factors, is required to produce viral mRNAs and new genomes. All stages of the life cycles of SARS-CoV-2 rely on host factors (Kim et al., 2020; Zhou et al., 2020), and hundreds of human proteins have been found to interact with viral proteins (Bouhaddou et al., 2020; Davidson et al., 2020; Gordon et al., 2020; Li et al., 2021).

In their large-scale proteomic analysis, Gordon et al. identified SARS-CoV-2 proteins interacting with human proteins involved in innate immune pathways, host translation machinery, cullin ubiquitin ligase, and bromodomain proteins (Gordon et al., 2020). Li and coworkers also identified 286 potential host targets using quantitative proteomic analysis approaches on SARS-CoV-2 intra-viral protein-protein interactions and virus-host interaction networks in human cells (Li et al., 2021). These findings further outline how the host cell infrastructure and metabolism ultimately determine the viral progeny.

In this section, we emphasize the importance of IDRs in SARS-CoV-2 by scrutinizing biochemical, structural, and virological experimental studies of selected viral proteins (Table 1), whose function includes IDRs/IDPs involvement in the host signaling machinery. However, the complete molecular mechanism of interaction of the virus protein with host proteins is not mentioned here because it is outside the scope of this review.

As was said earlier, intrinsically disordered protein regions evolve rapidly, promoting diversity and enabling interaction with multiple proteins among species (Ortiz et al., 2013; Chang et al., 2014) (Gitlin et al., 2014). In SARS-CoV-2, ORF6 is one of the second-highest IDR-containing accessory proteins. ORF6 hijacks nucleocytoplasmic mRNA transport factors Nucleoporin 98 (NUP98) and RNA export factor 1 (RAE1) (Miorin et al., 2020; Miyamoto et al., 2022; Kato et al., 2021). Using its C-terminal residues directly binds to transcription factors, signal transducers, and activators of transcription (STAT1) and inhibits its nuclear localization, therefore changing subcellular localization and resulting in downregulation of the interferon (IFN) pathway (Miyamoto et al., 2022; Lei et al., 2020). Importantly, this protein contains a long MoRF region (residues 26–61) near the C-terminal region (Giri et al., 2021), that matches with the residues 46–61 comprising trafficking motifs and with putative NUP98–RAE1 binding sequence (Gordon et al., 2020).

IDPs have gained great attention and opened new insights for understanding the molecular mechanism of diseases beyond the classic structure-function paradigm. Nowadays, the structural and functional characterization of IDPs and IDRs is becoming essential and thus unveiling the roles of protein disorder in protein-protein and protein-nucleic acid interactions is a promising field in understanding the biology of many diseases. Thus, understanding viral IDPs/IDRs and their molecular recognition features is essential for grasping their role in protein function and drug design, especially in light of the fact that SARS-CoV-2 variants arise within intrinsically disordered regions (Kulkarni et al., 2025; Gupta and Uversky, 2024).

One of the SARS-CoV-2 proteins bearing the highest content of intrinsically disordered regions is the multifunctional nucleoprotein N. Its major biological function depends on the interplay between the folded domains and the intrinsically disordered regions. Being the N protein a RNA packaging protein, the importance of its disordered regions in RNA binding and as major phosphorylation site, leads to consider the IDRs of the N protein potential areas for future studies to develop therapeutics. As such, though the SR-rich intrinsically disordered region is identified as a preferential binding site to human 14-3-3 protein (Del et al., 2021), little is known about the fundamental biology of this region.

Thus, the host-viral interacting IDPs/IDRs could be targeted for different therapeutic strategies.

Indeed, the survival of the virus inside the host cell is guaranteed by the dynamic molecular interactions of intrinsically disordered regions of Nsp1 and host ribosome subunits; this protein hijacks the host ribosome, through the intrinsically disordered C-terminal domain and thereby leads to host gene shutoff. The fully comprehension of the Nsp1 role in SARS-CoV-2 pathogenesis definitely needs the characterization of Nsp1 structural and dynamical properties along with its molecular interactions.

Gordon et al. reported a comprehensive SARS-CoV-2 PPI network, and the drug-human target network, suggesting that SARS-CoV-2 proteins, such as Nsp8 and ORF6, whose interaction sequence comprises the IDR, show potential druggable targets (Gordon et al., 2020).

Mutations can significantly affect the physicochemical properties of proteins. For instance, it has been shown that mutations in the IDRs of N protein can have nonlocal impact and modulate thermodynamic stability, secondary structure, particle formation, protein oligomeric state, and LLPS (Nguyen et al., 2024). From another perspective, experimental studies demonstrated the impact of the spike protein D614G mutation that induces IDR-like segments to form “order–disorder” transition (Zhang et al., 2021; Dokainish and Sugita, 2023). It has been further revealed that the order-disorder transition of IDRs in VOCs, which are associated with characteristic mutations such as D614G in the proximity of IDRs, controls the spike structure and dynamics (Sinha and Roy, 2023). This scenario opens an opportunity to target IDRs as remote operational switches for alternative therapeutic interventions. Moreover, as discussed above, IDRs show a helical propensity that possibly forms druggable conformational states. Interestingly enough, a recent study revealed that a small molecule to be evaluated in a clinical trial selectively interacts with an IDR oligomerization, further offering an insight that condensation and oligomerization could serve as key factors in the development of inhibitors for IDRs (Bielskutė et al., 2025).

Overall, although the presence of disordered regions could explain difficulties with crystallization of full-length N and Nsp1 proteins, deciphering the structural nuances of these proteins can provide important clues about potential therapeutic targets. Therefore, future studies should be oriented toward understanding the detailed mechanisms of intra- and intermolecular interactions of IDRs that may help to guide structure based therapeutics against SARS-CoV-2.