DESC:DESCRIPTION:
Field of the invention:
[0001] The present disclosure generally relates to the technical field of antiviral therapeutics and, in particular relates to a proteolysis-targeting chimera (PROTAC) compound that prevents Human Immunodeficiency Virus (HIV) infection by targeting and degrading HIV capsid protein, thereby inhibiting viral particle packing that is critical for the viral replication and providing potential treatment for drug-resistant strains of HIV.
Background of the invention:
[0002] HIV infection represents a significant global health crisis, with over 38 million individuals living with the virus worldwide. While current antiretroviral therapies are capable of effectively suppressing HIV replication and significantly prolonging the lives of those infected, they do not provide a definitive cure for the infection. These therapies, which must be adhered to for life, can also impose a substantial financial burden on patients and healthcare systems alike. Furthermore, many of these treatments are associated with a range of side effects, including metabolic disorders, cardiovascular issues, and psychological impacts, which can affect patient adherence and overall quality of life. Consequently, the search for more effective and sustainable solutions to combat HIV is critical.
[0003] The HIV capsid protein (CA) plays a pivotal role in the viral replication cycle, serving as a protective shell for the viral genome and facilitating the assembly and release of new virions. This structural protein is essential for maintaining the integrity of the viral particle and ensuring successful infection of host cells. Despite the development of several drugs aimed at targeting CA, these pharmacological agents exhibit limited efficacy due to the rapid mutations that frequently occur within the viral genome. Such mutations can alter the structure and function of the capsid protein, rendering existing inhibitors less effective and compromising their ability to control viral replication.
[0004] Most of the therapeutics developed to inhibit CA function by binding to sites that interact with host proteins, thereby disrupting the interactions necessary for viral replication. However, the majority of these agents fail to completely inhibit CA, particularly in the presence of mutant strains, which can diminish their effectiveness. While numerous drugs have been designed to target CA, only a small subset has received clinical approval, and some of these are effective primarily during the later stages of HIV infection. This limitation underscores the necessity for new therapeutic strategies that can effectively target the virus at earlier stages and address the challenges posed by viral mutations.
[0005] The therapeutic efficacy of existing CA-targeting drugs is increasingly questioned in light of the rapid mutations observed within the HIV genome, which contribute to resistance. The capsid protein, being a major target for antiretroviral therapy, is under constant evolutionary pressure from these mutations, which can lead to a reduction in the effectiveness of treatment regimens. As a result, the ongoing emergence of drug-resistant strains of HIV complicates the treatment landscape, necessitating the development of innovative therapeutic approaches that can provide durable control over the virus.
[0006] However, most of the current antiretroviral drugs that target CA bind to the host protein binding site on the capsid, leading to potential disruptions in the natural interactions between the capsid and host cellular machinery. However, there are still persisting problems such as toxicity and the accelerated development of drug resistance among the viral population. Moreover, many of these drugs are unable to fully inhibit the activity of the capsid protein, particularly in cases where the capsid has mutated. This inability to effectively control CA can contribute to the persistence in viral replication, ultimately resulting in the progression of HIV infection to AIDS. The limitations of existing treatments highlight the urgent need for alternative therapeutic strategies that can effectively disrupt HIV replication without the associated drawbacks of current approaches.
[0007] Therefore, there is a need for a proteolysis-targeting chimera (PROTAC) compound that prevents Human Immunodeficiency Virus (HIV) infection by targeting and degrading HIV capsid protein, thereby inhibiting viral replication and providing potential treatment for drug-resistant strains of HIV. There is also a need for a PROTAC compound that can directly or indirectly impact viral replication, thereby facilitating a potential cure for the infection at early stages, such as cases involving mutant strains. Further, there is also a need for PROTAC compound that targets HIV capsid protein regardless of its rapid mutagenesis, thus preventing viral infection more effectively and addressing the critical gaps in current HIV treatment paradigms.
Objectives of the invention:
[0008] The primary objective of the present invention is to develop a proteolysis-targeting chimera (PROTAC) compound that prevents Human Immunodeficiency Virus (HIV) infection by targeting and degrading HIV capsid protein, thereby inhibiting viral particle packing, replication and providing potential treatment for drug-resistant strains of HIV.
[0009] Another objective of the invention is to synthesize a PROTAC compound that remains effective against various mutant strains of HIV, thereby addressing the challenge of rapid viral mutations and enhancing the overall efficacy of HIV treatment.
[0010] The other objective of the invention is to synthesize a PROTAC compound that facilitates early intervention in the HIV infection cycle by degrading the capsid protein, thus preventing the establishment of persistent infection and reducing the likelihood of disease progression to AIDS.
[0011] The other objective of the invention is to synthesize a PROTAC compound that minimizes adverse effects commonly associated with existing antiretroviral therapies by employing a targeted mechanism of action that avoids disrupting host protein interactions while effectively degrading the target protein.
[0012] The other objective of the invention is to synthesize a PROTAC compound that improves treatment efficacy in spite of poor patient adherence to therapy and enhances overall treatment outcomes by providing a more effective and potentially curative approach to HIV treatment.
[0013] Yet another objective of the invention is to synthesize a PROTAC compound that expands therapeutic options available for HIV treatment, thereby contributing to the ongoing global efforts to combat HIV/AIDS and improve the quality of life for individuals living with the virus.
[0014] Further objective of the invention is to synthesize a PROTAC compound that facilitates development of combination therapy strategies by integrating the PROTAC-based approach with existing antiretroviral drugs, thereby potentially leading to more comprehensive and effective treatment regimens.
Summary of the invention:
[0015] The present disclosure proposes a proteolysis-targeting chimera (PROTAC) compound for preventing HIV infection and method of synthesizing the same. The following presents a simplified summary in order to provide a basic understanding of some aspects of the claimed subject matter. This summary is not an extensive overview. It is not intended to identify key/critical elements or to delineate the scope of the claimed subject matter. Its sole purpose is to present some concepts in a simplified form as a prelude to the more detailed description that is presented later.
[0016] In order to overcome the above deficiencies of the prior art, the present disclosure is to solve the technical problem to provide a proteolysis-targeting chimera (PROTAC) compound that prevents Human Immunodeficiency Virus (HIV) infection by targeting and degrading HIV capsid protein, thereby inhibiting viral replication and providing potential treatment for drug-resistant strains of HIV.
[0017] According to an aspect, the invention proposes a proteolysis-targeting chimera (PROTAC) compound that can directly or indirectly impact viral replication, thereby facilitating a potential cure for the infection at early stages, such as cases involving mutant strains. The PROTAC compound targets HIV capsid protein regardless of its rapid mutagenesis, thus preventing viral infection more effectively and addressing the critical gaps in current HIV treatment paradigms.
[0018] In one embodiment herein, the PROTAC compound comprises a targeting molecule that binds to HIV capsid protein (CA), a recruiting molecule that binds to human ubiquitin E3-ligase enzyme, and at least one polymeric linker that connects the targeting molecule and the recruiting molecule.
[0019] In one embodiment herein, the targeting molecule comprises at least one of small molecules, peptides, and antibodies that bind to the HIV capsid protein (CA). The recruiting molecule comprises at least one of pomalidomide (or) thalidomide (or) lenalidomide, which are known to interact with the human ubiquitin E3-ligase enzyme. The polymeric linker comprises at least one of ethylene glycol and polyethylene glycol (PEG).
[0020] In one embodiment herein, the recruiting molecule facilitates addition of a polyubiquitin chain to the HIV capsid protein by the human ubiquitin E3-ligase enzyme, thereby targeting the HIV capsid protein for degradation by human proteasome, which leads to complete degradation of the HIV capsid protein and subsequent inhibition of HIV viral replication for preventing the HIV infection.
[0021] According to an aspect, a method is disclosed for synthesizing the PROTAC compound. First, at one step, a three-dimensional (3D) structure of the HIV capsid protein is downloaded from a protein data bank. At another step, the downloaded 3D structure is processed to remove solvent and ligand molecules bound to the HIV capsid protein. At another step, the processed 3D structure is utilized as a drug target to screen small molecules, thereby identifying hit molecules, such as BRS01001 molecule and BRS01002 molecule, with high docking scores.
[0022] At another step, molecular dynamics simulations are performed to analyze the binding affinities of the identified hit molecules. At another step, the BRS01001 and BRS01002 molecules are selected as the targeting molecules that bind to the HIV capsid protein and the pomalidomide (or) thalidomide (or) lenalidomide molecule as the recruiting molecule that binds to the human ubiquitin E3-ligase enzyme. Further, at another step, the targeting molecule and the recruiting molecule are connected using at least one polymeric linker to synthesize the PROTAC compound.
[0023] Further, objects and advantages of the present invention will be apparent from a study of the following portion of the specification, the claims, and the attached drawings.
Detailed description of drawings:
[0024] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate an embodiment of the invention, and, together with the description, explain the principles of the invention.
[0025] FIG. 1 illustrates a schematic diagram depicting the interaction between the PROTAC compound, HIV capsid, and E3 ligase, in accordance to an exemplary embodiment of the invention.
[0026] FIG. 2 illustrates a schematic diagram showing the E3 ligase tagging the HIV capsid protein with an ubiquitin chain, in accordance to an exemplary embodiment of the invention.
[0027] FIG. 3 illustrates a schematic diagram showing the PROTAC compound targeting and degrading the HIV capsid protein, in accordance to an exemplary embodiment of the invention.
[0028] FIGs. 4A-4G illustrate schematic schemes showing compounds BRS01001 molecule and multiple PROTAC variants, in accordance to an exemplary embodiment of the invention.
[0029] FIG. 5 illustrates a molecular diagram showing the targeting molecule of the PROTAC compound docked into the binding pocket of the HIV capsid protein, in accordance to an exemplary embodiment of the invention.
[0030] FIG. 6 illustrates a graphical representation showing the binding affinities of different PROTAC compound variants to the HIV capsid protein, in accordance to an exemplary embodiment of the invention.
[0031] FIG. 7 illustrates a graphical representation showing Root Mean Square Deviations (RMSD) of the protein-ligand complex over time, in accordance to an exemplary embodiment of the invention.
[0032] FIG. 8 illustrates a graphical representation showing the Root Mean Square Fluctuations (RMSF) of the HIV capsid protein over time, in accordance to an exemplary embodiment of the invention.
[0033] FIG. 9 illustrates a graphical representation showing the types of interactions between the BRS01001 molecule and the HIV capsid protein over a 25 ns simulation, in accordance to an exemplary embodiment of the invention.
[0034] FIG. 10 illustrates a graphical representation showing the BRS01001 molecule surrounded by the HIV capsid protein, in accordance to an exemplary embodiment of the invention.
[0035] FIG. 11 illustrates a flowchart of a method for synthesizing the PROTAC compound, in accordance to an exemplary embodiment of the invention.
Detailed invention disclosure:
[0036] Various embodiments of the present invention will be described in reference to the accompanying drawings. Wherever possible, same or similar reference numerals are used in the drawings and the description to refer to the same or like parts or steps.
[0037] The present disclosure has been made with a view towards solving the problem with the prior art described above, and it is an object of the present invention to provide a proteolysis-targeting chimera (PROTAC) compound that prevents Human Immunodeficiency Virus (HIV) infection by targeting and degrading HIV capsid protein, thereby inhibiting viral replication and providing potential treatment for drug-resistant strains of HIV.
[0038] According to an example embodiment of the invention, FIG. 1 refers to a schematic diagram 100 depicting the interaction between the PROTAC compound, HIV capsid, and E3 ligase. In one embodiment herein, the proteolysis-targeting chimera (PROTAC) compound can directly or indirectly impact viral replication, thereby facilitating a potential cure for the infection at early stages, such as cases involving mutant strains. The PROTAC compound targets HIV capsid protein regardless of its rapid mutagenesis, thus preventing viral infection more effectively and addressing the critical gaps in current HIV treatment paradigms.
[0039] In one embodiment herein, the proteolysis-targeting chimera (PROTAC) compound is designed to effectively combat Human Immunodeficiency Virus (HIV) infection through a strategic combination of molecular components. The PROTAC compound comprises a targeting molecule that binds to the HIV capsid protein (CA), which is critical for the virus's structural integrity and functionality.

[0040] Additionally, the PROTAC compound includes a recruiting molecule that binds to the human ubiquitin E3-ligase enzyme, which is essential in the cellular process of protein degradation.

[0041] In one embodiment herein, the connection between the targeting molecule and the recruiting molecule is facilitated by at least one polymeric linker, which serves to maintain the structural integrity of the PROTAC compound while enhancing its efficacy. This unique arrangement allows the PROTAC compound to effectively bring the ubiquitin-proteasome system into action for targeting the HIV capsid protein for degradation, thus preventing the virus from packing, replicating and spreading.
[0042] In one embodiment herein, the targeting molecule of the PROTAC compound comprises at least one of small molecules, peptides, and antibodies that are designed to bind to the HIV capsid protein (CA). This diversity in the targeting molecule allows for a tailored approach to inhibiting HIV, as each type of binding agent may interact with the HIV capsid protein in different ways, thereby providing multiple avenues for therapeutic efficacy.
[0043] In one embodiment herein, the recruiting molecule includes well-characterized compounds such as pomalidomide (or) thalidomide (or) lenalidomide, all of which have established interactions with the human ubiquitin E3-ligase enzyme. These recruiting molecules are essential for tagging the HIV capsid protein for degradation. Furthermore, the polymeric linker may comprise at least one of ethylene glycol and/or polyethylene glycol (PEG), both of which are known for their biocompatibility and ability to enhance the solubility and stability of therapeutic agents. The incorporation of such linkers ensures that the PROTAC compound remains effective in physiological conditions, thereby maximizing its potential as a therapeutic agent against HIV.
[0044] According to an exemplary embodiment of the invention, FIG. 2 refers to a schematic diagram 200 showing the E3 ligase tagging the HIV capsid protein with an ubiquitin chain. In one embodiment herein, the recruiting molecule facilitates the addition of a polyubiquitin chain to the HIV capsid protein through the action of the human ubiquitin E3-ligase enzyme. This tagging process is essential because it marks the HIV capsid protein for degradation by the human proteasome, a cellular complex responsible for breaking down ubiquitinated proteins.
[0045] According to an exemplary embodiment of the invention, FIG. 3 refers to a schematic diagram 300 showing the PROTAC compound targeting and degrading the HIV capsid protein. As a result of this targeted degradation, there is complete degradation of the HIV capsid protein, which directly disrupts the virus's ability to replicate and assemble new viral particles. Consequently, this mechanism leads to the subsequent inhibition of HIV viral replication, thereby effectively preventing the HIV infection from progressing. By leveraging the ubiquitin-proteasome system, the PROTAC compound targets the viral capsid protein for destruction and also enhances the therapeutic efficacy against the HIV, thereby representing a novel approach to tackling this persistent and challenging viral infection.
[0046] According to an exemplary embodiment of the invention, a step-by-step process is disclosed for synthesizing the proteolysis-targeting chimera (PROTAC) compound. The synthesis process begins by downloading a three-dimensional (3D) structure of the HIV capsid protein (CA) from a reputable protein database, such as the Protein Data Bank (PDB). This database provides structural information derived from experimental techniques such as X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. The 3D structure serves as the foundational reference for understanding how potential ligands may interact with the capsid protein, thereby making it a first step in the design of the PROTAC compound.
[0047] Once the 3D structure is obtained, the next step involves processing the downloaded 3D structure to enhance its suitability for subsequent analysis. This processing includes the removal of any solvent molecules and ligand molecules that may be bound to the HIV capsid protein. By eliminating these extraneous elements, the resulting 3D structure is streamlined for focused studies on the capsid protein itself, thereby ensuring that any docking or screening conducted can be directed toward the relevant binding sites.
[0048] After the cleaning, the processed 3D structure is then utilized as a drug target to screen small molecules. This screening is performed using various molecular docking software tools that assess how well small molecules interact with the HIV capsid protein. BRS01001 molecule and BRS01002 molecule are identified as “hit” molecules in this screening process due to their strong binding affinities and favorable docking scores with the capsid protein.
[0049] Following the identification of the hit molecules, molecular dynamics simulations are performed to analyze their binding affinities and the stability of their interactions with the HIV capsid protein. This computational approach allows researchers to observe how the identified molecules behave in a simulated biological environment over time. The results of these simulations provide insights into the dynamic nature of the binding interactions and confirm the suitability of the hit molecules for further development into the PROTAC compound.
[0050] Based on the results of the molecular dynamics simulations, the targeting molecule is chosen for its ability to specifically bind to the HIV capsid protein, while the recruiting molecule is selected for its capacity to bind to the human ubiquitin E3-ligase enzyme. For instance, the BRS01001 or BRS01002 molecule may be selected as the targeting molecule, and the pomalidomide (or) thalidomide (or) lenalidomide molecule as the recruiting molecule. This careful selection process ensures that the final PROTAC compound is optimized for efficacy in targeting HIV.
[0051] Once the targeting and recruiting molecules are identified, the next step involves connecting these molecules using at least one polymeric linker. This polymeric linker maintains the spatial relationship between the two molecules, thereby allowing them to function synergistically. Common choices for the polymeric linker include at least one of ethylene glycol and polyethylene glycol (PEG), which enhance the stability and solubility of the PROTAC compound. The coupling of these molecules through the polymeric linker is typically accomplished using standard organic chemistry techniques, thus ensuring a stable and effective final product.
[0052] After the synthesis of the PROTAC compound is complete, the final step is purifying the obtained PROTAC compound. This purification is essential to eliminate any by-products or unreacted materials from the synthesis process. Various purification techniques, such as high-performance liquid chromatography (HPLC) or column chromatography, can be employed to isolate the pure PROTAC compound. The purified compound is then characterized using analytical methods, such as mass spectrometry and nuclear magnetic resonance (NMR), to confirm its identity and structural integrity.
[0053] According to an exemplary embodiment of the invention, FIGs. 4A-4G refer to schematic schemes 400, 402, 404, 406, 408, 410, and 412 showing the compounds BRS01001 molecule and multiple PROTAC variants. In one embodiment herein, these compounds are proteolysis-targeting chimeras (PROTACs) designed to target and degrade the HIV capsid protein. The synthesis begins with two starting materials, such as (2-methyl-1H-indol-3-yl)acetic acid, and (2S)-2-amino-3-phenylpropanoic acid. The two starting materials are coupled together using a condensation reaction to form a new compound. This compound has the structure 2-[2-(2-methyl-1H-indol-3-yl)acetamido]-3-phenylpropanoic acid.
[0054] In one embodiment herein, the R group in this compound can be modified to create different variants of the PROTAC. The different R groups are H (BRS01001) as shown in FIG. 4A, Ethyleneglycol (EG) + Pomalidomide (PROTAC01001) as shown in FIG. 4B, 2 x EG + Pomalidomide (PROTAC01002) as shown in FIG. 4C, 3 x EG + Pomalidomide (PROTAC01003) as shown in FIG. 4D, 4 x EG + Pomalidomide (PROTAC01004) as shown in FIG. 4E, 5 x EG + Pomalidomide (PROTAC01005) as shown in FIG. 4F, and 6 x EG + Pomalidomide (PROTAC01006) as shown in FIG. 4G. The R group influences the properties of the PROTAC, such as its solubility and stability.
[0055] According to an exemplary embodiment of the invention, FIG. 5 refers to a schematic diagram 500 showing the targeting molecule of the PROTAC compound docked into the binding pocket of the HIV capsid protein. In one embodiment herein, the HIV capsid protein is represented in grey, and the targeting molecule is represented in red. The targeting molecule is shown to be fit well into the binding pocket, thereby suggesting that it might be a good candidate for further development as a potential drug for HIV infection.
[0056] According to an exemplary embodiment of the invention, FIG. 6 refers to a graphical representation 600 showing the binding affinities of different PROTAC compound variants to the HIV capsid protein. In one embodiment herein, the binding affinity is measured in kcal/mol, and a lower value indicates a stronger binding affinity. The targeting molecule, BRS01001, has a binding affinity of -8.20 kcal/mol. The PROTAC variants have improved binding affinities compared to the BRS01001 molecule. The binding affinities range from -9.50 kcal/mol to -10.90 kcal/mol. Among the PROTAC variants, PROTAC01006 has the strongest binding affinity to the HIV capsid protein, with a value of -10.90 kcal/mol.
[0057] According to an exemplary embodiment of the invention, FIG. 7 refers to a graphical representation 700 showing Root Mean Square Deviations (RMSD) of the protein-ligand complex over time. In one embodiment herein, the RMSD is a measure of the average distance moved by the atoms of the protein and the ligand over a time period of 25 ns. The protein RMSD increases significantly between 10 ns and 15 ns, thereby suggesting that the protein is undergoing a conformational change during this time. After 15 ns, the protein RMSD stabilizes, thus indicating that the protein has reached a stable conformation. The ligand RMSD remains relatively low throughout the simulation, thereby suggesting that BRS01001 molecule is bound stably in the binding pocket of the HIV capsid protein.
[0058] According to an exemplary embodiment of the invention, FIG. 8 refers to a graphical representation 800 showing the Root Mean Square Fluctuations (RMSF) of the HIV capsid protein over time. In one embodiment herein, the RMSF is a measure of the average displacement of the atoms of the protein from their equilibrium position. A high RMSF indicates that the protein is undergoing significant fluctuations, while a low RMSF indicates that the protein is relatively stable. Several peaks of RMSF are observed along the protein sequence. These peaks suggest that the corresponding regions of the protein are undergoing significant fluctuations. The fluctuations observed in the RMSF profile may indicate that the protein is undergoing conformational changes to accommodate the binding of the BRS01001 molecule.
[0059] According to an exemplary embodiment of the invention, FIG. 9 refers to a graphical representation 900 showing the types of interactions between the BRS01001 molecule and the HIV capsid protein over a 25 ns simulation. In one embodiment herein, the different types of interactions are hydrogen bonds, hydrophobic interactions, ionic interactions, and water bridges. The BRS01001 molecule forms a combination of hydrogen bonds, hydrophobic interactions, and water bridges with the HIV capsid protein. The presence of multiple interaction types suggests that the BRS01001 molecule is bound stably in the binding pocket of the HIV capsid protein. The interactions involve specific amino acid residues in the HIV capsid protein, including ASN 53, LEU 56, MET 66, LEU 69, LYS 70, ILE 73, ASN 74, ALA 77, ALA 105, and TYR 130.
[0060] According to an exemplary embodiment of the invention, FIG. 10 refers to a graphical representation 1000 showing the BRS01001 molecule surrounded by the HIV capsid protein. In one embodiment herein, the BRS01001 molecule is represented as a 2D structure, and the HIV capsid protein is represented as a surface. The surface represents the solvent-exposed surface of the protein. The BRS01001 molecule is completely surrounded by the HIV capsid protein, thereby indicating that it is buried within the binding pocket. The surface of the BRS01001 molecule is not exposed to the solvent, thus suggesting that it is tightly bound to the protein.
[0061] According to an exemplary embodiment of the invention, FIG. 11 refers to a flowchart 1100 of a method for synthesizing the PROTAC compound. First, at step 1102, the three-dimensional (3D) structure of the HIV capsid protein is downloaded from the protein database. At step 1104, the downloaded 3D structure is processed to remove the solvent and ligand molecules bound to the HIV capsid protein. At step 1106, the processed 3D structure is utilized as the drug target to screen the small molecules, thereby identifying the hit molecules, such as BRS01001 molecule and BRS01002 molecule, with high docking scores.
[0062] At step 1108, the molecular dynamics simulations are performed to analyze the binding affinities of the identified hit molecules. At step 1110, the BRS01001 molecule is selected as the targeting molecule that binds to the HIV capsid protein and the pomalidomide molecule as the recruiting molecule that binds to the human ubiquitin E3-ligase enzyme. Further, at step 1112, the targeting molecule and the recruiting molecule are connected using at least one polymeric linker to synthesize the PROTAC compound.
[0063] Numerous advantages of the present disclosure may be apparent from the discussion above. In accordance with the present disclosure, the proteolysis-targeting chimera (PROTAC) compound prevents Human Immunodeficiency Virus (HIV) infection by targeting and degrading HIV capsid protein, thereby inhibiting viral replication and providing potential treatment for drug-resistant strains of HIV. The PROTAC compound remains effective against various mutant strains of HIV, thereby addressing the challenge of rapid viral mutations and enhancing the overall efficacy of HIV treatment. The PROTAC compound facilitates early intervention in the HIV infection cycle by degrading the capsid protein, thus preventing the establishment of persistent infection and reducing the likelihood of disease progression to AIDS.
[0064] The PROTAC compound minimizes adverse effects commonly associated with existing antiretroviral therapies by employing a targeted mechanism of action that avoids disrupting host protein interactions while effectively degrading the target protein. The PROTAC compound improves patient adherence to therapy and enhances overall treatment outcomes by providing a more effective and potentially curative approach to HIV treatment. The PROTAC compound expands therapeutic options available for HIV treatment, thereby contributing to the ongoing global efforts to combat HIV/AIDS and improve the quality of life for individuals living with the virus. The PROTAC compound facilitates development of combination therapy strategies by integrating the PROTAC-based approach with existing antiretroviral drugs, thereby potentially leading to more comprehensive and effective treatment regimens.
[0065] It will readily be apparent that numerous modifications and alterations can be made to the processes described in the foregoing examples without departing from the principles underlying the invention, and all such modifications and alterations are intended to be embraced by this application.
,CLAIMS:CLAIMS:
I / We Claim:
1. A proteolysis-targeting chimera (PROTAC) compound for preventing Human Immunodeficiency Virus (HIV) infection, comprising:
a targeting molecule binds to HIV capsid protein (CA); and
a recruiting molecule binds to human ubiquitin E3-ligase enzyme,
wherein the targeting molecule and the recruiting molecule are connected by at least one polymeric linker.


2. The PROTAC compound as claimed in claim 1, wherein the recruiting molecule facilitates addition of a polyubiquitin chain to the HIV capsid protein by the human ubiquitin E3-ligase enzyme, thereby targeting the HIV capsid protein for degradation by human proteasome, which leads to complete degradation of the HIV capsid protein and subsequent inhibition of HIV viral particle packing and replication for preventing the HIV infection.
3. The PROTAC compound as claimed in claim 1, wherein the targeting molecule comprises at least one of small molecules, peptides, and antibodies that bind to the HIV capsid protein (CA).
4. The PROTAC compound as claimed in claim 1, wherein the recruiting molecule comprises at least one of pomalidomide, thalidomide, and lenalidomide, which are known to interact with the human ubiquitin E3-ligase enzyme.
5. The PROTAC compound as claimed in claim 1, wherein the at least one polymeric linker comprises at least one of ethylene glycol and polyethylene glycol (PEG).
6. A method for synthesizing a proteolysis-targeting chimera (PROTAC) compound, comprising:
downloading a three-dimensional (3D) structure of HIV capsid protein from a protein database;
processing the downloaded 3D structure to remove solvent and ligand molecules bound to the HIV capsid protein;
utilizing the processed 3D structure as a drug target to screen small molecules, thereby identifying hit molecules, such as BRS01001 molecule and BRS01002 molecule, with high docking scores;
performing molecular dynamics simulations to analyze the binding affinities of the identified hit molecules;
selecting the BRS01001 molecule as a targeting molecule that binds to the HIV capsid protein and the pomalidomide molecule as a recruiting molecule that binds to human ubiquitin E3-ligase enzyme; and
connecting the targeting molecule and the recruiting molecule using at least one polymeric linker to synthesize the PROTAC compound.
7. The method as claimed in 6, wherein the synthesized PROTAC compound is purified for use in preventing the HIV infection.