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Synthesis, Antiviral Potency, in Vitro ADMET, and X-ray Structure of Potent CD4 Mimics as Entry Inhibitors That Target the Phe43 Cavity of HIV-1 gp120.

Curreli F, Kwon YD, Belov DS, Ramesh RR, Kurkin AV, Altieri A, Kwong PD, Debnath AK
J Med Chem 60 3124-3153 (2017)
Cited: 23 times
EuropePMC logo PMID: 28266845

Abstract

In our attempt to optimize the lead HIV-1 entry antagonist, NBD-11021, we present in this study the rational design and synthesis of 60 new analogues and determination of their antiviral activity in a single-cycle and a multicycle infection assay to derive a comprehensive structure-activity relationship (SAR). Two of these compounds, NBD-14088 and NBD-14107, showed significant improvement in antiviral activity compared to the lead entry antagonist in a single-cycle assay against a large panel of Env-pseudotyped viruses. The X-ray structure of a similar compound, NBD-14010, confirmed the binding mode of the newly designed compounds. The in vitro ADMET profiles of these compounds are comparable to that of the most potent attachment inhibitor BMS-626529, a prodrug of which is currently undergoing phase III clinical trials. The systematic study presented here is expected to pave the way for improving the potency, toxicity, and ADMET profile of this series of compounds with the potential to be moved to the early preclinical development.

Articles - 5u6e mentioned but not cited (3)

  1. Structure-based lead optimization to improve antiviral potency and ADMET properties of phenyl-1H-pyrrole-carboxamide entry inhibitors targeted to HIV-1 gp120. Curreli F, Belov DS, Kwon YD, Ramesh R, Furimsky AM, O'Loughlin K, Byrge PC, Iyer LV, Mirsalis JC, Kurkin AV, Altieri A, Debnath AK. Eur J Med Chem 154 367-391 (2018)
  2. HIV-1 gp120 Antagonists Also Inhibit HIV-1 Reverse Transcriptase by Bridging the NNRTI and NRTI Sites. Losada N, Ruiz FX, Curreli F, Gruber K, Pilch A, Das K, Debnath AK, Arnold E. J Med Chem 64 16530-16540 (2021)
  3. Design of gp120 HIV-1 entry inhibitors by scaffold hopping via isosteric replacements. Iusupov IR, Curreli F, Spiridonov EA, Markov PO, Ahmed S, Belov DS, Manasova EV, Altieri A, Kurkin AV, Debnath AK. Eur J Med Chem 224 113681 (2021)


Reviews citing this publication (4)

  1. Pyrroles as Privileged Scaffolds in the Search for New Potential HIV Inhibitors. Bianco MDCAD, Marinho DILF, Hoelz LVB, Bastos MM, Boechat N. Pharmaceuticals (Basel) 14 893 (2021)
  2. Synthesis and Applications of Nitrogen-Containing Heterocycles as Antiviral Agents. Tran TN, Henary M. Molecules 27 2700 (2022)
  3. HIV-1 Entry Inhibitors: A Review of Experimental and Computational Studies. Mostashari Rad T, Saghaie L, Fassihi A. Chem Biodivers 15 e1800159 (2018)
  4. Small-Molecule HIV Entry Inhibitors Targeting gp120 and gp41. Yu F, Jiang S. Adv Exp Med Biol 1366 27-43 (2022)

Articles citing this publication (16)

  1. A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge. Madani N, Princiotto AM, Mach L, Ding S, Prevost J, Richard J, Hora B, Sutherland L, Zhao CA, Conn BP, Bradley T, Moody MA, Melillo B, Finzi A, Haynes BF, Smith Iii AB, Santra S, Sodroski J. Nat Commun 9 2363 (2018)
  2. Exploring the new potential antiviral constituents of Moringa oliefera for SARS-COV-2 pathogenesis: An in silico molecular docking and dynamic studies. Muhammad S, Hassan SH, Al-Sehemi AG, Shakir HA, Khan M, Irfan M, Iqbal J. Chem Phys Lett 767 138379 (2021)
  3. A Small-Molecule CD4-Mimetic Compound Protects Bone Marrow-Liver-Thymus Humanized Mice From HIV-1 Infection. Princiotto AM, Vrbanac VD, Melillo B, Park J, Tager AM, Smith AB, Sodroski J, Madani N. J Infect Dis 218 471-475 (2018)
  4. Preclinical Optimization of gp120 Entry Antagonists as anti-HIV-1 Agents with Improved Cytotoxicity and ADME Properties through Rational Design, Synthesis, and Antiviral Evaluation. Curreli F, Ahmed S, Benedict Victor SM, Iusupov IR, Belov DS, Markov PO, Kurkin AV, Altieri A, Debnath AK. J Med Chem 63 1724-1749 (2020)
  5. Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents. Mori M, Stelitano G, Chiarelli LR, Cazzaniga G, Gelain A, Barlocco D, Pini E, Meneghetti F, Villa S. Pharmaceuticals (Basel) 14 155 (2021)
  6. Synthesis, Antiviral Activity, and Structure-Activity Relationship of 1,3-Benzodioxolyl Pyrrole-Based Entry Inhibitors Targeting the Phe43 Cavity in HIV-1 gp120. Curreli F, Belov DS, Ahmed S, Ramesh RR, Kurkin AV, Altieri A, Debnath AK. ChemMedChem 13 2332-2348 (2018)
  7. Characterization of Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Variants Selected for Resistance to a CD4-Mimetic Compound. Anang S, Richard J, Bourassa C, Goyette G, Chiu TJ, Chen HC, Smith AB, Madani N, Finzi A, Sodroski J. J Virol 96 e0063622 (2022)
  8. Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor. Meuser ME, Rashad AA, Ozorowski G, Dick A, Ward AB, Cocklin S. Molecules 24 E1581 (2019)
  9. Antiviral Activity and Crystal Structures of HIV-1 gp120 Antagonists. Curreli F, Kwon YD, Nicolau I, Burgos G, Altieri A, Kurkin AV, Verardi R, Kwong PD, Debnath AK. Int J Mol Sci 23 15999 (2022)
  10. Design, synthesis, and antiviral activity of a series of CD4-mimetic small-molecule HIV-1 entry inhibitors. Curreli F, Ahmed S, Benedict Victor SM, Iusupov IR, Spiridonov EA, Belov DS, Altieri A, Kurkin AV, Debnath AK. Bioorg Med Chem 32 116000 (2021)
  11. Facile Synthesis of NH-Free 5-(Hetero)Aryl-Pyrrole-2-Carboxylates by Catalytic C-H Borylation and Suzuki Coupling. Kanwal S, Ann NU, Fatima S, Emwas AH, Alazmi M, Gao X, Ibrar M, Saleem RSZ, Chotana GA. Molecules 25 E2106 (2020)
  12. Rational Design of A Novel Small-Molecule HIV-1 Inactivator Targeting Both gp120 and gp41 of HIV-1. Pu J, Dai Y, Wang Q, Lu L, Zhang J, Xu W, Xie L, Wang S, Yu F, He X, Jiang S. Front Pharmacol 11 613361 (2020)
  13. Triazolyl Ru(II), Os(II), and Ir(III) complexes as potential HIV-1 inhibitors. Putterill B, Rono C, Makhubela B, Meyer D, Gama N. Biometals 35 771-784 (2022)
  14. Comparative Pharmacokinetics of a Dual Inhibitor of HIV-1, NBD-14189, in Rats and Dogs with a Proof-of-Concept Evaluation of Antiviral Potency in SCID-hu Mouse Model. Stoddart CA, Curreli F, Horrigan S, Altieri A, Kurkin AV, Debnath AK. Viruses 14 2268 (2022)
  15. In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4. Andrianov AM, Nikolaev GI, Kornoushenko YV, Xu W, Jiang S, Tuzikov AV. Viruses 11 E746 (2019)
  16. V3 tip determinants of susceptibility to inhibition by CD4-mimetic compounds in natural clade A human immunodeficiency virus (HIV-1) envelope glycoproteins. Anang S, Zhang S, Fritschi C, Chiu T-J, Yang D, Smith Iii AB, Madani N, Sodroski J. J Virol 97 e0117123 (2023)


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