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Binding mode characterization of NBD series CD4-mimetic HIV-1 entry inhibitors by X-ray structure and resistance study.

Curreli F, Kwon YD, Zhang H, Yang Y, Scacalossi D, Kwong PD, Debnath AK
Antimicrob Agents Chemother 58 5478-91 (2014)
Cited: 31 times
EuropePMC logo PMID: 25001301

Abstract

We previously identified two small-molecule CD4 mimetics--NBD-556 and NBD-557--and synthesized a series of NBD compounds that resulted in improved neutralization activity in a single-cycle HIV-1 infectivity assay. For the current investigation, we selected several of the most active compounds and assessed their antiviral activity on a panel of 53 reference HIV-1 Env pseudoviruses representing diverse clades of clinical isolates. The selected compounds inhibited tested clades with low-micromolar potencies. Mechanism studies indicated that they act as CD4 agonists, a potentially unfavorable therapeutic trait, in that they can bind to the gp120 envelope glycoprotein and initiate a similar physiological response as CD4. However, one of the compounds, NBD-09027, exhibited reduced agonist properties, in both functional and biophysical studies. To understand the binding mode of these inhibitors, we first generated HIV-1-resistant mutants, assessed their behavior with NBD compounds, and determined the X-ray structures of two inhibitors, NBD-09027 and NBD-10007, in complex with the HIV-1 gp120 core at ∼2-Å resolution. Both studies confirmed that the NBD compounds bind similarly to NBD-556 and NBD-557 by inserting their hydrophobic groups into the Phe43 cavity of gp120. The basic nitrogen of the piperidine ring is located in close proximity to D368 of gp120 but it does not form any H-bond or salt bridge, a likely explanation for their nonoptimal antagonist properties. The results reveal the structural and biological character of the NBD series of CD4 mimetics and identify ways to reduce their agonist properties and convert them to antagonists.

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  1. PRISM-EM: template interface-based modelling of multi-protein complexes guided by cryo-electron microscopy density maps. Kuzu G, Keskin O, Nussinov R, Gursoy A. Acta Crystallogr D Struct Biol 72 1137-1148 (2016)


Reviews citing this publication (6)

  1. Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41. Lu L, Yu F, Cai L, Debnath AK, Jiang S. Curr Top Med Chem 16 1074-1090 (2016)
  2. Small-molecule HIV-1 entry inhibitors targeting gp120 and gp41: a patent review (2010-2015). Li W, Lu L, Li W, Jiang S. Expert Opin Ther Pat 27 707-719 (2017)
  3. Driving HIV-1 into a Vulnerable Corner by Taking Advantage of Viral Adaptation and Evolution. Harada S, Yoshimura K. Front Microbiol 8 390 (2017)
  4. Opening the HIV envelope: potential of CD4 mimics as multifunctional HIV entry inhibitors. Laumaea A, Smith AB, Sodroski J, Finzi A. Curr Opin HIV AIDS 15 300-308 (2020)
  5. Implications of Fragment-Based Drug Discovery in Tuberculosis and HIV. Mallakuntla MK, Togre NS, Santos DB, Tiwari S. Pharmaceuticals (Basel) 15 1415 (2022)
  6. Small-Molecule HIV Entry Inhibitors Targeting gp120 and gp41. Yu F, Jiang S. Adv Exp Med Biol 1366 27-43 (2022)

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  1. Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds. Madani N, Princiotto AM, Zhao C, Jahanbakhshsefidi F, Mertens M, Herschhorn A, Melillo B, Smith AB, Sodroski J. J Virol 91 e01880-16 (2017)
  2. Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds. Madani N, Princiotto AM, Easterhoff D, Bradley T, Luo K, Williams WB, Liao HX, Moody MA, Phad GE, Vázquez Bernat N, Melillo B, Santra S, Smith AB, Karlsson Hedestam GB, Haynes B, Sodroski J. J Virol 90 5031-5046 (2016)
  3. Homology models of the HIV-1 attachment inhibitor BMS-626529 bound to gp120 suggest a unique mechanism of action. Langley DR, Kimura SR, Sivaprakasam P, Zhou N, Dicker I, McAuliffe B, Wang T, Kadow JF, Meanwell NA, Krystal M. Proteins 83 331-350 (2015)
  4. The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site. Prévost J, Tolbert WD, Medjahed H, Sherburn RT, Madani N, Zoubchenok D, Gendron-Lepage G, Gaffney AE, Grenier MC, Kirk S, Vergara N, Han C, Mann BT, Chénine AL, Ahmed A, Chaiken I, Kirchhoff F, Hahn BH, Haim H, Abrams CF, Smith AB, Sodroski J, Pazgier M, Finzi A. mBio 11 e00280-20 (2020)
  5. Peptide Triazole Inactivators of HIV-1 Utilize a Conserved Two-Cavity Binding Site at the Junction of the Inner and Outer Domains of Env gp120. Aneja R, Rashad AA, Li H, Kalyana Sundaram RV, Duffy C, Bailey LD, Chaiken I. J Med Chem 58 3843-3858 (2015)
  6. Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity. Curreli F, Kwon YD, Zhang H, Scacalossi D, Belov DS, Tikhonov AA, Andreev IA, Altieri A, Kurkin AV, Kwong PD, Debnath AK. J Med Chem 58 6909-6927 (2015)
  7. 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)
  8. 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)
  9. 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)
  10. Computational Evaluation of HIV-1 gp120 Conformations of Soluble Trimeric gp140 Structures as Targets for de Novo Docking of First- and Second-Generation Small-Molecule CD4 Mimics. Moraca F, Acharya K, Melillo B, Smith AB, Chaiken I, Abrams CF. J Chem Inf Model 56 2069-2079 (2016)
  11. 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)
  12. Synthesis, antiviral activity and resistance of a novel small molecule HIV-1 entry inhibitor. Curreli F, Haque K, Xie L, Qiu Q, Xu J, Yong W, Tong X, Debnath AK. Bioorg Med Chem 23 7618-7628 (2015)
  13. 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)
  14. Computational identification of novel entry inhibitor scaffolds mimicking primary receptor CD4 of HIV-1 gp120. Andrianov AM, Kashyn IA, Tuzikov AV. J Mol Model 23 18 (2017)
  15. 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)
  16. 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)
  17. 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)
  18. Virtual Screening, Biological Evaluation, and 3D-QSAR Studies of New HIV-1 Entry Inhibitors That Function via the CD4 Primary Receptor. Zhang C, Zhang H, Huang LS, Zhu S, Xu Y, Zhang XQ, Schooley RT, Yang X, Huang Z, An J. Molecules 23 E3036 (2018)
  19. 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)
  20. Specific Noncovalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small-Molecule CD4 Mimetics and HIV-1 gp120. Moraca F, Rinaldo D, Smith AB, Abrams CF. ChemMedChem 13 627-633 (2018)
  21. Synthesis of oxalamides by acceptorless dehydrogenative coupling of ethylene glycol and amines and the reverse hydrogenation catalyzed by ruthenium. Zou YQ, Zhou QQ, Diskin-Posner Y, Ben-David Y, Milstein D. Chem Sci 11 7188-7193 (2020)
  22. 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)
  23. Strain-Dependent Activation and Inhibition of Human Immunodeficiency Virus Entry by a Specific PF-68742 Stereoisomer. Zhao C, Princiotto AM, Nguyen HT, Zou S, Zhao ML, Zhang S, Herschhorn A, Farrell M, Pahil K, Melillo B, Sambasivarao SV, Abrams C, Smith AB, Madani N, Sodroski J. J Virol 93 e01197-19 (2019)
  24. 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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