INTRODUCTION:

K. Barry Sharpless discovered click chemistry in 2001 and this chemistry has been changing the drug development process by offering a highly effective, adaptive, and selective chemical synthesis process since then ¹. The three defining elements of click chemistry are: ease of use, strength, and bio-orthogonality. The reactions of click chemistry are fast and highly yielding and highly flexible regarding the various circumstances under which the reaction takes place. The triazole linkage that it gives is stable and has thus become the most widely used model. It finds extensive applications within the pharmaceutical sector in (CuAAC).

The application of click chemistry in the field of drug discovery has increased greatly in the recent past, thus allowing functionalization of biologically active mixtures and quick assembly of drug-like atoms ². It has been useful in the creation of novel subatomic structures, precise drug delivery systems, and complicated particles, such as therapeutic peptides and derivatives of regular items. Owing to the fantastic efficiency of click chemistry in conjugating small particles to biomolecules such as proteins, DNA, and antibodies, it improved the targeting accuracy of drugs and significantly minimized adverse side effects and optimized the treatment.

Today, click chemistry is being employed in the drug-making process regarding the synthesis of prodrugs and ADCs. The utilization of click reactions has actually allowed scientists to target lethal drugs to antibodies with greater accuracy, which in turn allows anti-disease drugs to be more precise ³. Likewise, the power of click chemistry has made it easier to formulate delivery systems such as hydrogels and nanoparticles, wherein the controlling of some medications can be made over a specific area. Moreover, a sub-class of click reactions called bio-symmetrical reactions have studied the tagging and tracking of biomolecules in vivo, which presented potential applications in personalized therapy and diagnostics.

The click chemistry versatility does expand further beyond the medication search and discovery frontiers. The pool of utility for this fantastic resource becomes even greater by investigating some other click reactions other than CuAAC, namely SPAAC and sulfur-fluoride exchange known as SuFEx ⁴. These developments enhance the overall security efficacy, and specificity of therapeutic specialties while streamlining the drug manufacture method. This has now put click chemistry at the forefront of modern pharmaceutical research and applications, ranging from early-stage drug discovery to clinical drug development and beyond.

CLICK CHEMISTRY

A very effective and modular method of chemical synthesis, click chemistry concentrates on producing complicated compounds via straightforward and dependable reactions. Chemists Carolyn Bertozzi, K. Barry Sharpless, and Morten Meldal initially used the word in the early 2000s to refer to a group of reactions that were fast-moving and selective, producing large yields with little by-products ⁵. The azide-alkyne cycloaddition, which yields 1,2,3-triazoles, is a famous reaction in click chemistry. It is an environmentally benign reaction that takes place in mild environments and frequently involves water. The reactions are usually characterized by their chemo selectivity, which makes it easy to purify and isolate the products because only particular functional groups react under the circumstances utilized. Click chemistry is very useful in drug development, bioconjugation, and materials science because of its modularity, which makes it easier to quickly assemble a variety of molecular architectures. It helps scientists to link biomolecules for imaging or therapeutic applications, build libraries of chemicals for screening, and produce new materials with specific features ⁶. Furthermore, click chemistry has revolutionized sectors like polymer science, nanotechnology, and regenerative medicine by creating new pathways for the construction of complex nanostructures and biomaterials. Because of click chemistry's effectiveness, dependability, and adaptability, it has become a mainstay of contemporary synthetic chemistry, fostering interdisciplinary collaboration and fostering creative responses to challenging problems.

CLICK CHEMISTRY IN DRUG DISCOVERY

Click chemistry represents a breakthrough in the drug discovery area, with finding a series of efficient, selective, and versatile chemical transformations capable of rapidly assembling complex molecular architectures out of simple precursors ⁷. The method, as pioneered by many other famous chemists, such as Carolyn Bertozzi, is becoming increasingly popular due to its potential to create diverse libraries as well as consistency in reaction outcome. By allowing the exploitation of click chemistry, the drug discovery process is expedited: the timeline and cost involved in classical drug discovery can be reduced.

The Concept and Advantages of Click Chemistry

Click chemistry finds strength in biorthogonal reactions-that is, reactions that can take place inside living systems without interfering with native biochemical processes. Typically, these reactions are high-yielding, easily carried out, and yield stable products ⁸. A characteristic of click chemistry is the use of modular building blocks, which makes it possible for researchers to systematically access a rich array of compounds. This modular approach simplifies the synthesis of diverse chemical libraries, facilitating high-throughput screening for discovering new drug candidates.

One of the major advantages of click chemistry is that it allows for improvement in the solubility, stability, and selectivity of drug candidates. The methodology introduced has the potential to introduce many functional groups into lead compounds ⁹. Thus, researchers are able to fine-tune the pharmacological properties of drug candidates by optimizing these properties, which ultimately will give better efficacy against biological targets and also improved pharmacokinetics, such as absorption, distribution, metabolism, and excretion (ADME) features.

Click chemistry has several roles in the context of drug discovery. First, it allows the production of libraries of compounds that are supposed to be screened against known biological targets, thereby accelerating synthesis and optimization of leads during lead optimization ¹⁰. Click chemistry can also be used to prepare novel chemical entities that may facilitate more complex interactions within biological systems. This capability has led to its ability to become a primary tool of contemporary medicinal chemistry.

Applications of Click Chemistry in Target Identification and Modulation

One of the largest applications of click chemistry in drug discovery is in the design of modulators of specific protein targets ¹¹. An excellent example of this application is the validation of compounds against peroxisome proliferator-activated receptor-γ (PPAR-γ) structures, such as in Figure 1. The role of PPAR-γ in glucose and lipid metabolism has been significant; its implication in metabolic disorders, particularly type 2 diabetes, has been noteworthy as well.

This will be possible if the small molecules that act as PPAR-γ agonists and antagonists are synthesized using a wide variety of chemical scaffolds through click chemistry. It will thus help find an optimal therapeutic profile by such identification ¹². Due to this possibility of creating a highly diverse library of potential modulators, compounds can be selected which can selectively activate or inhibit PPAR-γ for treating diabetes and various other related conditions.

Figure 1: One of the chemicals evaluated for peroxisome proliferator-activated receptor-γ structure

Enhancing Biorthogonal Strategies in Living Systems

Incorporating biorthogonal click chemistry reactions into drug discovery research further extends the attractiveness of this approach ¹³. Biorthogonal reactions, such as azide-alkyne cycloaddition, enable the selective labelling of biomolecules in complex biological environments. This gives scientists the ability to track the distribution and dynamics of drug candidates in real time, which is a very important insight into their mechanism of action, metabolic pathways, and interactions with cellular targets.

A great example is attaching fluorescent tags to drug candidates via bioorthogonal reactions, which allows for the visualization of their localization within cells or tissues ¹⁴. Such real-time monitoring can inform subsequent design iterations, and this can therefore result in the optimization of drug candidates based on observed behavior in biological systems. Such insights are precious in terms of understanding how modifications in chemical structures impact drug efficacy and safety.

Development of Novel Peptidomimetics and Macrocyclic Compounds

Click chemistry has also led to the synthesis of new peptidomimetics and macrocyclic compounds that possess a higher efficacy and stability of the therapeutic agent. Typical peptides are normally associated with drawbacks related to poor bioavailability as well as susceptibility to enzymatic degradation ¹⁵. Click chemistry has allowed the design of cyclic structures and other more complex forms that exactly mimic nature but show great stability compared to traditional peptides.

For example, cyclic peptides prepared by click chemistry are designed to be stable at the bioactive conformation of their linear precursors but at the cost of conformational flexibility, thus increasing the binding affinity to target proteins ¹⁶. Improved stability and potency are what force cyclic peptides into therapeutic applications as potential candidates in diseases like cancers, infectious diseases, and metabolic disorders.

Future Directions and Challenges

With the shifting landscape of drug discovery, incorporation of click chemistry into traditional workflows is promising to yield innovative therapeutic agents. The simplicity and efficiency of click reactions will most likely influence their adoption across various stages of drug development, starting from target identification to lead optimization ¹⁷. However, current click chemistry methodologies are hobbled by oxidative damage to biomolecules and sensitive functional groups. All these problems have to be solved to correctly use the potential of click chemistry in drug discovery.

Click chemistry emerged as a versatile and highly effective tool for drug discovery - highly suitable for the rapid generation of libraries of compound diversity and optimization of lead compounds ¹⁸. The utility of click chemistry for therapeutic development is well illustrated by the example of testing compounds against PPAR-γ structures, such as those shown in Figure 1. Its further development and integration into drug discovery workflows are likely to continue to promote our understanding of drug-target interactions and, thus, improve patient outcomes across a wide spectrum of diseases.

RECENT ADVANCES IN THE CUAAC CLICK HERE TO LEARN HOW CHEMISTRY APPLIES TO DRUG DISCOVERY

1,2,3-Triazole as a Bio isosteric Substitute for Specific Functional Groups

CuAAC click chemistry has made tremendous advancements within the realm of drug discovery, primarily through a 1,2,3-triazole used as a bio isostere to many functional groups ¹⁹. Bio isosterism describes the replacement of a functional group within a molecule with another functional group that has been demonstrated to exhibit, under specific conditions, virtually identical physical or chemical properties, thereby conserving the biological activity of the molecule under consideration and likely enhancing the pharmacological profile. In this respect, the 1,2,3-triazole ring offers a characteristic profile of richness as an effective and versatile alternative, essentially due to its unique electronic and steric properties ²⁰. Its aromatic character, hydrogen bonding capacity, and ability to participate in π-π stacking interactions make it a desirable candidate in enhancing binding affinity and selectivity in drug candidates.

For instance, as illustrated in Figure 2, parazole replaced by a bioisosterically mimicked compound containing 1,2,3-triazole revealed a selective σ (1) receptor ligand. Thus, while retaining the biological activity of the parent ligand, this targeted replacement resulted in an improvement of the compound's selectivity toward the target receptor without the introduction of off-target effects ²¹. Interaction of the triazole moiety with the σ (1) receptor enhanced the selectivity and diminished off-target effects. Such developments further elucidate the possibility of triazole modification of existing pharmacophores in producing more potent therapeutic agents.

Figure 2: Discovering a selective σ (1) receptor ligand by substituting 1,2,3-triazole for parazole in a bio isosteric manner.

Besides acting as a good substituent, 1,2,3-triazole can further be used as an amide bio isostere. In Figure 3, it shows the generation of a novel class of potent HIV-1 Vif antagonists by the replacement of the classical amide linkage with 1,2,3-triazole. This not only helped to preserve the right biological activity that is required for the antagonistic effect but also provided metabolic stability toward hydrolysis ²². Introduction of the triazole functionality by researchers led to considerable improvement in the activities of these antagonists with lower IC50 values than their amide counterparts. This illustrates that 1,2,3-triazole is a very versatile bio isosteric functional group in designing drugs to finely control the molecular properties with ideal therapeutic effects.

Figure 3: Finding a novel class of very effective HIV-1 Vif antagonists by employing 1,2,3-triazole as an amide bio isostere.

New achievements in CuAAC click chemistry, specifically those gained by substituting with 1,2,3-triazole as a bio isosteric substitute, make it especially useful to improve the discovery and development of new drugs ²³. Its unique properties can be used to generate molecules that present better selectivity, potency, and stability, thus ending up with better treatments for diseases.

1,2,3-Triazole as a linker unit of pharmacophore elements

A 1,2,3-triazole ring thus finds its identity as an important linker unit in pharmacophore design, enhancing extremely important properties and functionalities of quite a few drug candidates. It is a biorthogonal and versatile group which provides unparalleled advantages in drug discovery, notably in optimizing molecular interactions, improving pharmacokinetic profiles, and tailoring overall therapeutic efficacy of compounds ²⁴. As a linker unit, it not only connects disparate pharmacophoric elements but also stabilizes them and furthers the interaction with biological targets, thereby making this molecule extremely valuable in modern medicinal chemistry.

As illustrated in Figure 4, optimization of boronic acids as β-lactamase inhibitors represents an example of the application of 1,2,3-triazoles as linkers. Along these lines, the use of the triazole linker has enabled the preparation of a series of inhibitors with potent class C β-lactamases inhibitory activity through the assembly of different functional groups ²⁵. The design was strategic because a small library of compounds could be synthesized and quickly screened to significantly improve on binding affinity and selectivity toward the active site of β-lactamase. It is in this way that triazole linking can improve the pharmacophoric landscape of a compound, translation into more potently inhibitory profiles and thus greater therapeutic potential.

Figure 4: Lead optimization of boronic acids via click chemistry as β-lactamase inhibitors

An example is the application of triazole linkers for the identification of benzofuro[3,2-b] quinolone derivatives as particular stabilizers of the c-myc G-quadruplex ²⁶. The introduction of 1,2,3-triazole as a linker between pharmacophoric elements led to a new series of compounds that possessed high selectivity and affinity towards the G-quadruplex DNA structure. The triazole linkage coordinated different functional groups and allowed the compounds obtained through it necessary conformational flexibility to interact effectively with the target, thus stabilizing G-quadruplex and potentially influencing gene expression. It alluded to the possibility of the triazole linker facilitating the design of specific compounds interacting selectively with nucleic acid structures, opening the way for innovative therapeutic strategies ²⁷.

Figure 5: Benzofuro's discovery[3,2-b] Click chemistry to use quinolone derivatives as c-myc G-quadruplex-specific stabilizers.

Also, as shown in Figure 6, the identification of a new oral prolyl hydroxylase inhibitor, [3-hydroxy-5-(1H-1,2,3-triazol-4-yl)picolinoyl]glycines, through click-chemistry interface is in fact an example of how the triazole ring could be useful as a linker unit ²⁸. This compound exhibited favorable safety profiles and indeed proved to be able to stabilizes a crucial target for the treatment of anemia through hypoxia-inducing factor stabilization. Incorporation of the triazole moiety into the compound rendered stability to it and increased its potency along with bioavailability. This example further illustrates the potential utility of triazolates as pivotal linkers in compound design toward specific therapeutic targets that may be improving performance in the biological system.

Figure 6: An Oral Inhibitor of Prolyl Hydroxylase with Advantageous Safety Profiles: [3–Hydroxy-5–(1H–1,2,3–triazol-4–yl)picolinoyl]glycines Determined Through a Click-Chemistry Interface

Figure 7 exhibits triazole derivatives that inhibit Keap1-Nrf2 protein-protein interaction but activate Nrf2-dependent gene products identified using the platform of click chemistry as well as in silico docking simulations ²⁹. The employment of triazole as a linker in such molecules thus enabled a set of small molecules to now be produced that would strongly disrupt the Nrf2 interaction with its negative regulator, Keap1. It leads to enhanced expression of cytoprotective genes, thereby underlining the therapeutic potential of triazole-linked compounds in managing oxidative stress-related diseases. Here, the triazole linker connects pharmacophoric elements but optimizes interactions within the cellular environment, thereby being versatile in enhancing drug action.

Figure 7: Triazole compounds that suppress Keap1-Nrf2 protein-protein interaction and stimulate Nrf2-dependent gene products have been found using click chemistry and in silico docking simulations.

The 1,2,3-triazole ring is an excellent linker unit in the design of a pharmacophore element that has fundamentally impacted drug discovery and development. One can envisage it holding different functional groups together within a pharmacophore, enhancing selectivity and binding affinity and tailoring pharmacokinetic properties to make it an important component in the manufacture of new therapeutics against several disease targets ³⁰. As shown in examples in figures such as 4, 5, 6, and 7, it is remarkably evident that incorporation of 1,2,3-triazole can provide new avenues for medicinal chemistry, which opens a way to further effective treatment.

1,2,3-Triazole as a peptidomimetic

The 1,2,3-triazole moiety has become a promising peptidomimetic in drug discovery. It provides a versatile and robust framework to mimic structures of peptides but is also equipped with stability, bioavailability, and specificity that could not be found in the conventional peptide systems ³¹. Because it has come into the design of peptidomimetics to be structurally mimetic to their desired function, replacing conventional enzymatic degradation and poor membrane permeability, the researchers develop compounds that may naturally maintain pharmacological properties required for the desired effect while offering other therapeutic advantages.

A fine example is provided in Figure 8, which lists the design of novel epoxide incorporating peptidomimetics as selective calpain inhibitors through the help of click chemistry ³². Calpains are a family of calcium-dependent cysteine proteases that are involved in many cellular processes. Their dysregulation has been implicated in many diseases, including neurodegenerative disorders. In principle, the use of 1,2,3-triazoles as peptidomimetic units in this regard enables one to rationally design compounds with peptidomimetic properties potentially inhibitory to calpain activity. The flexibility and robustness of triazole linkers stabilize the compounds against proteolytic degradation and thus are good candidates for therapeutic intervention ³³. Using the power of click chemistry, researchers will rapidly synthesize and screen a library of triazole-based peptidomimetics to identify strong calpain inhibitors of significant clinical importance.

Figure 8: Click chemistry was utilized to develop novel epoxide-incorporating peptidomimetics that function as selective calpain inhibitors.

Figure 9 illustrates the side-chain-to-side-chain cyclization combined with click chemistry as a novel route to cyclic peptide triazoles from peptide 17. This kind of strategy has proven effective for the generation of cyclic compounds that show higher affinity and specificity towards their targets ³⁴. Studies assessing the capacity of these cyclic triazole peptides to prevent the interaction of gp120 with either the sCD4 or the 17b antibody used SPR analyses and calculated IC50 values in order to compare their inhibitory activities. The pink highlights in the sequences of compounds 18 and 19 illustrate parts of peptide 17 that are carried through to reveal how structural features may be preserved in the process of cyclicization, which can increase the pharmacological qualities of the compound. The cyclic triazoles derived from these cyclications not only show appreciable inhibition of gp120 activity but also illustrate the flexibility of 1,2,3-triazoles in peptidomimetics design able to effectively modulate protein-protein interactions in HIV-1 ³⁵.

Figure 9: A new side-chain-to-side-chain cyclization and click chemistry application is used to produce cyclic peptide triazoles from peptide 17. The ability of the peptides to block gp120 from binding to either the sCD4 or to the 17b antibody was established with SPR analysis of the compounds. The compounds gave IC50 values. Regions of peptide 17 remaining in compounds 18 and 19 are highlighted in pink in their respective sequences.

Figure 10 shows a melanocortin receptor agonist synthesized through click chemistry, indicating that 1,2,3-triazoles may have a significant place as linkers in targeted receptor therapeutic agents ³⁶. Melanocortin receptors are involved in some of the most basic physiological processes, including appetite, energy homeostasis, and inflammation. Triazole linkers, thus contained within the design of the agonist, allow for a higher interaction with the receptor but also support stability and solubility rather than an agonist with a traditional peptide-based backbone. This strategic alteration not only enhances the receptor selectivity but also the overall therapeutic index of the compounds ³⁷. Mimicking peptide functionality while avoiding the inherent limitations of peptides highlights the importance of 1,2,3-triazoles as peptidomimetics for the development of new therapeutic medicines.

Figure 10: An agonist of melanocortin receptors synthesized by click chemistry.

The main drug discovery benefits in the use of 1,2,3-triazoles as peptidomimetics are on account of stability, bioavailability, and specificity improvements. Click chemistry and cyclization techniques enabled innovative preparations that translate the desired biological activity of peptides into improvements in their pharmacological profiles ³⁸. The examples in Figures 8, 9, and 10 show the potential of 1,2,3-triazole-based peptidomimetics as pan or class-selective probes against alternative biological pathways or therapies for a wide variety of diseases.

Quick identification of bioactive compounds by in situ screening and click chemistry-based combinatorial libraries.

The production and biological assay of hit congeners yield information for SAR, which is generated iteratively and used to uncover bioactive mixtures. Regardless, hit-to-lead studies are costly and time-consuming due to the tedious and time-consuming nature of traditional methodologies ³⁹. Instead, a robust mechanism for developing SARs and discovering lead compounds through combinatorial library-based chemical diversity discovery is provided using CuAAC click-chemistry and in situ screening.

Figure 11: Using a click-chemistry high-throughput technology, new flavonoid dimers are discovered to reverse mrp1-mediated drug resistance in malignancies.

CuAAC click chemistry developments recently have made it possible to successfully assemble a 300-compound library of flavonoid dimers, which may be MRP1 modulators ⁴⁰. Compound 28 stood out among the rest for its exceptional efficacy and safety, showing an EC50 value of 53 nM after high-throughput screening for MRP1 regulation and cytotoxicity. Furthermore, compound 28 showed improved pharmacokinetic characteristics (refer to Figure 11). CuAAC has the potential to be an effective tool for speeding up the creation and characterisation of chemical libraries for biological assessment, as demonstrated by this study. Still, oxidative degradation to biomolecules and sensitive functional groups in existing CuAAC-based combinatorial libraries remains a significant concern that may impede further progress in this field ⁴¹.

Tethering in situ click chemistry

Tethering in situ click chemistry has been considered as a novel approach toward drug discovery and development, aiming to identify and optimize highly specific and selective bioactive compounds ⁴². Biorthogonal reactions that promote the formation of stable small-molecule-biomolecule conjugates in the biological context enable researchers to study complex interactions in living systems. By using this approach, scientists would be well-equipped to interrogate their native protein targets and eventually result in the discovery of new inhibitors as well as therapeutic agents.

In the tethering in situ click chemistry principle, the idea is to construct a stable linkage between a small molecule and a biomolecule of interest, which in this case is usually a protein ⁴³. A process starts with the identification of a target protein, beginning with the design and synthesis of the small molecule probes that can interact with a target. This approach involves the click chemistry component, which ensures rapid and efficient reactions with high-purity products without extensive purification steps ⁴⁴. This is highly advantageous, especially in biological settings where conventional chemical methods would be hindered by competing reactions or undesirable by-products.

A significant application of in situ click chemistry tethering is in the development of cell-permeable inhibitors of O-GlcNAc transferase, as exemplified in Figure 12. The figure in question highlights the potential of kinetic target steering in constructing such inhibitors that act to regulate a broad number of cellular processes by means of their mechanism established through the process of O-GlcNAcylation of proteins ⁴⁵. OGT is an enzyme that catalyzes the transfer of O-GlcNAc moieties to serine and threonine residues on target proteins, thereby affecting their stability, localization, and activity. Aberrant regulation of OGT has been implicated in multiple diseases, including cancer and neurodegenerative disorders, so it has potential for therapy as a target ⁴⁶.

Figure 12: Kinetic target steering is used in the manufacture of cell-permeable O-GlcNAc transferase inhibitors.

Researchers synthesized a series of cell-permeable inhibitors of the enzyme O-GlcNAc transferase through tethering in situ click chemistry ⁴⁷. Kinetic target steering in such an approach helps control the binding interaction between the inhibitors and their target enzyme in order to find compounds bearing the desired pharmacokinetic properties. This process increases the specificity of inhibitors but simultaneously can also limit off-target effects, thereby enhancing their therapeutic potential.

Such tethering also identifies inhibitors but readily permits SAR studies through facile systematic modification of small molecule probes and their evaluation for target binding and biological activity ⁴⁸. Such an iterative cycle is important for optimizing lead compounds with improved efficacy and safety.

In situ click chemistry offers an effective strategy for advanced drug discovery, in synthesis and optimization of the bioactive compounds ⁴⁹. The researchers may check an interaction at the complex biology level; it ultimately comes up with new inhibitors to fine-tune key biological processes. The synthesis of cell-permeable O-GlcNAc transferase inhibitors, as illustrated in Figure 12, represents the applicability of this strategy to aid in furthering therapeutic intervention within the treatment of a myriad of diseases through modulation of critical enzymatic pathways ⁵⁰. This novel strategy stands poised to increase the scope of drug leads within the pharmaceutical space through novel avenues of therapeutic intervention.

CONCLUSION:

In the field of drug research, click chemistry has emerged as a game-changer, providing a quick, effective, and flexible method for creating and refining pharmacological blends. Its exceptional selectivity and bio-symmetrical properties have rendered it indispensable in the development of innovative molecular platforms, drug delivery mechanisms, and targeted therapies, such as antibody-drug conjugates and nanoparticles. The most widely used reaction is still (CuAAC), which has been instrumental in the production of prodrugs, catalyst inhibitors, and potent antibacterial and antiviral agents. Continued developments, such as the investigation of substitute click reactions such as (SuFEx) and strain-promoted azide-alkyne cycloaddition (SPAAC), have broadened the scope of uses and improved medication efficiency, safety, and accuracy. Click chemistry is an essential tool in today's pharmacological research because it has the potential to spur additional advancements in drug discovery and therapeutic development as it develops.

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Received on 05.01.2025 Revised on 19.03.2025

Accepted on 22.04.2025 Published on 02.05.2025

Available online from May 07, 2025

Research J. Pharmacy and Technology. 2025;18(5):2416-2424.

DOI: 10.52711/0974-360X.2025.00345

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