Nucleocapsid Protein: A Desirable Target for Future Therapies Against HIV-1

  • Mattia Mori
  • Lesia Kovalenko
  • Sébastien Lyonnais
  • Danny Antaki
  • Bruce E. TorbettEmail author
  • Maurizio BottaEmail author
  • Gilles MirambeauEmail author
  • Yves MélyEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 389)


HIV reverse transcription and nucleocapsid. After the capsid has entered the cell, reverse transcriptase (A) creates a DNA copy (green) of the HIV RNA genome (yellow), using a cellular transfer RNA (B) as a primer. HIV nucleocapsid protein (C) acts as a chaperone to unfold the RNA secondary structure. The ribonuclease activity of RT removes the viral RNA after the DNA strand is created. Interaction of HIV Vif (D) with cellular APOBEC (E) is also shown

The currently available anti-HIV-1 therapeutics is highly beneficial to infected patients. However, clinical failures occur as a result of the ability of HIV-1 to rapidly mutate. One approach to overcome drug resistance is to target HIV-1 proteins that are highly conserved among phylogenetically distant viral strains and currently not targeted by available therapies. In this respect, the nucleocapsid (NC) protein, a zinc finger protein, is particularly attractive, as it is highly conserved and plays a central role in virus replication, mainly by interacting with nucleic acids. The compelling rationale for considering NC as a viable drug target is illustrated by the fact that point mutants of this protein lead to noninfectious viruses and by the inability to select viruses resistant to a first generation of anti-NC drugs. In our review, we discuss the most relevant properties and functions of NC, as well as recent developments of small molecules targeting NC. Zinc ejectors show strong antiviral activity, but are endowed with a low therapeutic index due to their lack of specificity, which has resulted in toxicity. Currently, they are mainly being investigated for use as topical microbicides. Greater specificity may be achieved by using non-covalent NC inhibitors (NCIs) targeting the hydrophobic platform at the top of the zinc fingers or key nucleic acid partners of NC. Within the last few years, innovative methodologies have been developed to identify NCIs. Though the antiviral activity of the identified NCIs needs still to be improved, these compounds strongly support the druggability of NC and pave the way for future structure-based design and optimization of efficient NCIs.


Long Terminal Repeat Virtual Screening Nuclear Magnetic Resonance Spectroscopy Isothermal Titration Calorimetry Nucleocapsid Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Antiretroviral drugs




Cytotoxic concentration50


Drug resistance


Effective concentration50


Human immunodeficiency virus




Long terminal repeat




Nucleocapsid inhibitor


Primer-binding site


Protease inhibitor


Polypurine tract




Packaging element


Reverse transcriptase


Reverse transcriptase complex


Spacer peptide 1


Spacer peptide 2


Trans-activation response element


Trans-activator of transcription


Unique 5′ sequence


Untranslated region


Zinc finger



This work was supported by the European Project THINPAD “Targeting the HIV-1 Nucleocapsid Protein to fight Antiretroviral Drug Resistance” (FP7—Grant Agreement 601969), ANRS, NIGMS (P50GM103368), and the HIVE Center. G.M. and S.L. are greatly indebted to Jose Maria Gatell for his kind hosting and support of the AIDS Research Group (IDIBAPS).


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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Dipartimento di Biotecnologie Chimica e FarmaciaUniversità degli Studi di SienaSienaItaly
  2. 2.Laboratoire de Biophotonique et Pharmacologie UMR 7213 CNRS, Faculté de PharmacieUniversité de StrasbourgIllkirch CedexFrance
  3. 3.Department of ChemistryKyiv National Taras Shevchenko UniversityKyivUkraine
  4. 4.AIDS Research GroupIDIBAPSBarcelonaSpain
  5. 5.Department of Molecular and Experimental Medicine and HIV Interaction and Viral Evolution CenterThe Scripps Research InstituteLa JollaUSA
  6. 6.Sbarro Institute for Cancer Research and Molecular MedicineTemple UniversityPhiladelphiaUSA
  7. 7.Faculté de BiologieUniversité Pierre et Marie Curie, Sorbonne UniversitésParisFrance

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