The Future of HIV-1 Therapeutics pp 53-92

Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 389)

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

Chapter

Abstract

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.

Abbreviations

ARDs

Antiretroviral drugs

CA

Capsid

CC50

Cytotoxic concentration50

DR

Drug resistance

EC50

Effective concentration50

HIV

Human immunodeficiency virus

IN

Integrase

LTR

Long terminal repeat

MA

Matrix

NCI

Nucleocapsid inhibitor

PBS

Primer-binding site

PI

Protease inhibitor

PPT

Polypurine tract

PR

Protease

Ψ

Packaging element

RT

Reverse transcriptase

RTC

Reverse transcriptase complex

SP1

Spacer peptide 1

SP2

Spacer peptide 2

TAR

Trans-activation response element

Tat

Trans-activator of transcription

U5

Unique 5′ sequence

UTR

Untranslated region

ZF

Zinc finger

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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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