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Anti-HIV Screening Libraries

Combination antiretroviral therapy is the key approach to reducing the viral load in HIV-infected people [1-4]. Generally, it incorporates several medications with different activity types into an HIV treatment regimen, which curbs the infection and prevents its progression to AIDS. However, the problem of HIV resistance to known and accepted drugs has emerged [5]. This makes the discovery and development of new and effective small-molecule drugs for antiretroviral treatment even more urgent than ever.

In response to this acute need, Life Chemicals has contributed to antiretroviral research with its proprietary set of Anti-HIV Screening Libraries:

The PAINS filters were not applied to the compound selection since this would have cut out many relevant analogs of known antiretroviral inhibitors from the reference sets, as those were originally not PAINS-compliant. However, such filtering can be done at the customer’s request.

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

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  Examples of approved anti-HIV infection drugs and similar compounds from the Life Chemicals Library.

 

Figure 1. Examples of approved anti-HIV infection drugs and similar compounds from the Life Chemicals Library.

Background

The multidrug strategy has become highly effective and usable over the years, having successfully enhanced the quality of life for HIV-positive individuals. Around 50 approved HIV medicines [6] may serve as components of a personalized treatment regimen. Depending on a viral target and active substance, they form seven main drug classes [7]. Various medications operate at different stages of the HIV life cycle [8]: some of them prevent the virus from entering the immune system cells; others can block enzymes that HIV needs to replicate – reverse transcriptase, protease, and integrase.

This variability of options stems from over 30 years of intense research efforts. However, the ability to control HIV as a chronic disease is just a step toward complete recovery. The cure remains one of the greatest medical challenges, which motivates a continuous search for innovative anti-HIV drugs and treatment strategies.

Anti-HIV Focused Library

Designed with a 2D fingerprint similarity approach, this Screening Library contains over 19,600 drug-like screening compounds with potential antiretroviral activity.

The reference compound set was extracted from the ChEMBL and BindingDB databases. Thoroughly selected molecules constitute the basis for work on target-specific HIV inhibitors targeting HIV-related proteins, cell lines, or the whole virus (Fig. 2). The compounds were chosen from the Life Chemicals HTS Compound Collection using the 75 % similarity cut-off (Tanimoto) on MDL public keys fingerprints.

Among the selected compounds, there are potential inhibitors of the following HIV-specific molecular targets:

  • Aberrant vpr protein
  • Anti-repression transactivator
  • Envelope glycoprotein gp160
  • Envelope polyprotein GP160
  • HIV1 integrase
  • HIV1 protease
  • HIV1 reverse transcriptase
  • HIV1 Tat protein
  • HIV1 enhancer-binding protein 1

Compound distribution targeting organism- and single protein targets within the HIV Focused Library

Figure 2. Compound distribution targeting organism- and single protein targets within the HIV Focused Library

Anti-HIV Targeted Library

This Screening Set contains about 2,600 structurally-diverse screening molecules with potential activity against the following HIV-focused drug targets:

The drug-like compounds were picked out by high-throughput virtual screening based on the pharmacophore hypothesis. A more detailed description of each compound subset for specific antiretroviral protein targets can be found below.

The virus can remain in the central nervous system and reproduce, thus leading to neurological disorders. This may be due to the inability of anti-HIV drugs to cross the blood-brain barrier and inhibit HIV in the brain, which is critical to reversing or ameliorating HIV-related neurocognitive impairment [9]. Therefore, the Anti-HIV Targeted Library compounds were filtered according to their ability to adsorb and penetrate the blood-brain barrier, also taking into account the parameter of metabolism, i.e., their ability to be excreted from the body.

Groups of anti-HIV drugs and mechanisms of their action

Figure 3. Groups of anti-HIV drugs and mechanisms of their action [10]

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a protease that enhances BCL10-induced activation, resulting in the activation of NF-kappa-B and p38 MAP kinases [11], which stimulate the expression of genes encoding proinflammatory cytokines and chemokines. The protease is also involved in the induction of T helper 17 differentiation [12] and mediates the cleavage of N4BP1 in T cells after TCR-mediated activation, which leads to the inactivation of N4BP1. Since N4BP1 inhibits the replication of human immunodeficiency virus 1 (HIV1), MALT1-mediated inactivation of N4BP1 facilitates the reactivation of latent HIV1 proviruses [13]. Thus, MALT1 is a relevant target for targeted HIV therapy.

Key features:

  • Method: high-throughput virtual screening
  • X-Ray data used: 4MXO
  • Filters applied: metabolism, QPPCaco, QPlogBB, QPPMDCK, PercentHuman-OralAbsorption
  • Number of compounds selected: 821

Pharmacophore hypothesis based on the complex of MALT1 with inhibitor

Figure 4. Pharmacophore hypothesis based on the complex of MALT1 with inhibitor

Proto-oncogene tyrosine-protein kinase Src (SRC)

Proto-oncogene tyrosine-protein kinase Src is a non-receptor tyrosine kinase. It presents a component of many signaling pathways that control various processes within the cell [14], in particular, gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation [15-16]. A potential role of the proto-oncogene tyrosine-protein kinase Src in the development of HIV infection has also been identified. It is known that after contact with human CD4 cells, HIV induces autophosphorylation of the protein tyrosine kinase 2 beta (PTK2B) inside the cell. Autophosphorylation of PTK2B at Tyr402 occurs with the participation of c-SRCs, which leads to focal adhesion and remodeling of the CD4 cell cytoskeleton. Thus, inhibiting the activity or expression of the proto-oncogene, tyrosine-protein kinase Src can reduce the level of HIV infection, making this protein a promising target for HIV treatment [9, 17].

Key features:

  • Method: high-throughput virtual screening
  • X-Ray data used: 4I1R
  • Filters applied: metabolism, QPPCaco, QPlogBB, QPPMDCK, PercentHuman-OralAbsorption
  • Number of compounds selected: 780

Pharmacophore hypothesis based on the complex of SRC with inhibitor

Figure 5. Pharmacophore hypothesis based on the complex of SRC with inhibitor

HIV-1 Protease

HIV protease is an enzyme involved in the hydrolysis of peptide bonds in retroviruses. It plays an essential part in the HIV life cycle, as it splits proteins into smaller units and uses them to create the mature protein components of an infectious HIV virion [18]. Inhibition of HIV protease disrupts the ability of the retrovirus to replicate and infect other cells.

The mature HIV protease is a 22 kDa homodimer, each subunit consisting of 99 amino acids. The active site is located between the identical subunits and contains the sequence of the catalytic triad (Asp25, Thr26, and Gly27) [19]. HIV protease performs two main essential functions: the HIV pre-protease is responsible for auto-processing, and the mature protease can hydrolyze peptide bonds on Gag-Pol polyproteins at nine specific sites, converting the resulting subunits into mature, fully functional proteins [20]. The HIV protease can mutate in two major ways: in the active site and the periphery of the protein, thus impairing binding to the inhibitor [21]. Considering this fact, the search for new and effective drugs targeting HIV protease is of great importance in the pharmaceutical industry.

Key features:

  • Method: high-throughput virtual screening
  • X-Ray data used: 7DOZ
  • Filters applied: metabolism, QPPCaco, QPlogBB, QPPMDCK, PercentHuman-OralAbsorption
  • Number of compounds selected: 517

Pharmacophore hypothesis based on the complex of HIV-1 protease with inhibitor

Figure 6. Pharmacophore hypothesis based on the complex of HIV-1 protease with inhibitor

HIV-1 Reverse Transcriptase

HIV reverse transcriptase (HIV RT) is one of the enzymes used by the retrovirus for self-copying. This enzyme catalyzes the conversion of single-stranded viral RNA into proviral DNA, which further infects the host cell DNA [22, 23]. Its inhibition allows hindering virus replication. Corresponding targeted drugs (nucleoside and non-nucleoside reverse transcriptase inhibitors) exclude reverse transcriptase from the infectious process by either blocking it or altering its structure.

HIV reverse transcriptase consists of two subunits of 51 and 66 kDa [24]. This reverse transcriptase has three consecutive biochemical activities: RNA-dependent DNA polymerase activity, ribonuclease H (RNase H), and DNA-dependent DNA polymerase activity. Functioning together, these activities allow the enzyme to convert single-stranded RNA into double-stranded complementary DNA [25]. HIV reverse transcriptase is currently one of the most important targets in the treatment of AIDS. However, mutations in the structure of HIV-1 RT can lead to appearing drug-resistant strains of the virus [26], making the development and clinical trials of new drugs even more imperative.

Key features:

  • Method: high-throughput virtual screening
  • X-Ray data used: 4I7F
  • Filters applied: metabolism, QPPCaco, QPlogBB, QPPMDCK, PercentHuman-OralAbsorption
  • Number of compounds selected: 538

Pharmacophore hypothesis based on the complex of HIV-1 reverses transcriptase with inhibitor

Figure 7. Pharmacophore hypothesis based on the complex of HIV-1 reverses transcriptase with inhibitor

 

References

  1. Lu, D. Y.; Wu, H. Y.; Yarla, N. S. et al. (2018). HAART in HIV/AIDS Treatments: Future Trends. Infect Disord Drug Targets 18(1):15‐22. DOI: 10.2174/1871526517666170505122800
  2. Maenza, J., Charles Flexner, C. (1998). Combination Antiretroviral Therapy for HIV Infection. Am Fam Physician 57(11):2789-2798. https://www.aafp.org/afp/1998/0601/p2789.html
  3. Pomerantz, R.J.; Horn, D.L. (2003). Twenty years of therapy for HIV-1 infection. Nat Med. 9, 867-873. DOI: 10.1038/nm0703-867
  4. Arts, E. J., & Hazuda, D. J. (2012). HIV-1 antiretroviral drug therapy. Cold Spring Harbor perspectives in medicine, 2(4), a007161. DOI: 10.1101/cshperspect.a007161
  5. Bandera A, Gori A, Clerici M, Sironi M. Phylogenies in ART: HIV reservoirs, HIV latency, and drug resistance. Curr Opin Pharmacol. 2019;48:24-32. doi:10.1016/j.coph.2019.03.003
  6. https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/21/58/fda-approved-HIV-medicines
  7. Maeda, K., Das, D., Kobayakawa, T., Tamamura, H., & Takeuchi, H. (2019). Discovery and Development of Anti-HIV Therapeutic Agents: Progress Towards Improved HIV Medication. Curr. Top. Med. Chem., 19(18), 1621–1649. DOI: 10.2174/1568026619666190712204603
  8. Saha, M., & Bhattacharya, S. (2019). Recent Developments in the Medicinal Chemistry for New Small-Molecule Therapeutics to Treat HIV-AIDS. Curr. Top. Med. Chem., 19(18), 1569–1570. DOI: 10.2174/156802661918191009110427
  9. Puhl AC, Garzino Demo A, Makarov VA, Ekins S. New targets for HIV drug discovery. Drug Discov Today. 2019;24(5):1139-1147. doi:10.1016/j.drudis.2019.03.013
  10. https://www.mdpi.com/cells/cells-10-01687/article_deploy/html/images/cells-10-01687-g002-550.jpg
  11. Zhang YY, Peng J, Luo XJ. Post-translational modification of MALT1 and its role in B cell- and T cell-related diseases. Biochem Pharmacol. 2022;198:114977. doi:10.1016/j.bcp.2022.114977
  12. Wang Q, Wang Y, Liu Q, et al. MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in rheumatoid arthritis. Front Immunol. 2022;13:913830. Published 2022 Jul 28. doi:10.3389/fimmu.2022.913830
  13. Yamasoba D, Sato K, Ichinose T, et al. N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation. Nat Microbiol. 2019;4(9):1532-1544. doi:10.1038/s41564-019-0460-3
  14. Wang Y, Cao H, Chen J, McNiven MA. A direct interaction between the large GTPase dynamin-2 and FAK regulates focal adhesion dynamics in response to active Src. Mol Biol Cell. 2011;22(9):1529-1538. doi:10.1091/mbc.E10-09-0785
  15. K Bhanumathy K, Balagopal A, Vizeacoumar FS, Vizeacoumar FJ, Freywald A, Giambra V. Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia. Cancers (Basel). 2021;13(2):184. Published 2021 Jan 7. doi:10.3390/cancers13020184
  16. Rivera-Torres J, San José E. Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential. Front Pharmacol. 2019;10:1011. Published 2019 Sep 18. doi:10.3389/fphar.2019.01011
  17. McCarthy SD, Sakac D, Neschadim A, Branch DR. c-SRC protein tyrosine kinase regulates early HIV-1 infection post-entry. AIDS. 2016;30(6):849-858. doi:10.1097/QAD.0000000000001028
  18. Voshavar, C. Protease inhibitors for the treatment of HIV/AIDS: Recent advances and future challenges. (2019). Curr. Top. Med. Chem., 19(18), 1571-1598. DOI: 10.2174/1568026619666190619115243
  19. Weber IT, Wang YF, Harrison RW. HIV Protease: Historical Perspective and Current Research. Viruses. 2021;13(5):839. Published 2021 May 6. doi:10.3390/v13050839
  20. Louis JM, Ishima R, Torchia DA, Weber IT. HIV-1 protease: structure, dynamics, and inhibition. Adv Pharmacol. 2007;55:261-298. doi:10.1016/S1054-3589(07)55008-8
  21. Shah D, Freas C, Weber IT, Harrison RW. Evolution of drug resistance in HIV protease. BMC Bioinformatics. 2020;21(Suppl 18):497. Published 2020 Dec 30. doi:10.1186/s12859-020-03825-7
  22. Xavier Ruiz, F., & Arnold, E. (2020). Evolving understanding of HIV-1 reverse transcriptase structure, function, inhibition, and resistance. Current Opinion in Structural Biology, 61, 113–123. DOI: 10.1016/j.sbi.2019.11.011
  23. Wang, Y., De Clercq, E., & Li, G. (2019). Current and emerging non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 treatment. Expert Opinion on Drug Metabolism & Toxicology. 15:10, 813-829, DOI: 10.1080/17425255.2019.1673367
  24. Xavier Ruiz F, Arnold E. Evolving understanding of HIV-1 reverse transcriptase structure, function, inhibition, and resistance. Curr Opin Struct Biol. 2020;61:113-123. doi:10.1016/j.sbi.2019.11.011
  25. London RE. HIV-1 Reverse Transcriptase: A Metamorphic Protein with Three Stable States. Structure. 2019;27(3):420-426. doi:10.1016/j.str.2018.11.011
  26. Cilento ME, Kirby KA, Sarafianos SG. Avoiding Drug Resistance in HIV Reverse Transcriptase. Chem Rev. 2021;121(6):3271-3296. doi:10.1021/acs.chemrev.0c00967
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