Unprocessed Viral DNA Could Be the Primary Target of the HIV-1 Integrase Inhibitor Raltegravir
| Autor: | Serge Fermandjian, Zeina Hobaika, Safwat Abdel-Azeim, Farah F. Ammar, Loussinée Zargarian, Richard G. Maroun |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Drugs and Devices
Viral Diseases animal structures Biophysics lcsh:Medicine HIV Integrase Biochemistry Microbiology Virus chemistry.chemical_compound Raltegravir Potassium Virology Host chromosome Biochemical Simulations medicine Humans Drug Interactions HIV Integrase Inhibitors lcsh:Science Biology HIV Long Terminal Repeat Acquired Immunodeficiency Syndrome Multidisciplinary biology Oligonucleotide Topoisomerase lcsh:R DNA structure Computational Biology HIV DNA Raltegravir Molecular biology Pyrrolidinones Long terminal repeat Integrase Nucleic acids Infectious Diseases chemistry DNA Viral Viral Enzymes HIV-1 biology.protein Medicine lcsh:Q Research Article medicine.drug |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 7, p e40223 (2012) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0040223 |
| Popis: | Integration of HIV DNA into host chromosome requires a 3'-processing (3'-P) and a strand transfer (ST) reactions catalyzed by virus integrase (IN). Raltegravir (RAL), commonly used in AIDS therapy, belongs to the family of IN ST inhibitors (INSTIs) acting on IN-viral DNA complexes (intasomes). However, studies show that RAL fails to bind IN alone, but nothing has been reported on the behaviour of RAL toward free viral DNA. Here, we assessed whether free viral DNA could be a primary target for RAL, assuming that the DNA molecule is a receptor for a huge number of pharmacological agents. Optical spectroscopy, molecular dynamics and free energy calculations, showed that RAL is a tight binder of both processed and unprocessed LTR (long terminal repeat) ends. Complex formation involved mainly van der Waals forces and was enthalpy driven. Dissociation constants (Kds) revealed that RAL affinity for unbound LTRs was stronger than for bound LTRs. Moreover, Kd value for binding of RAL to LTRs and IC50 value (half concentration for inhibition) were in same range, suggesting that RAL binding to DNA and ST inhibition are correlated events. Accommodation of RAL into terminal base-pairs of unprocessed LTR is facilitated by an extensive end fraying that lowers the RAL binding energy barrier. The RAL binding entails a weak damping of fraying and correlatively of 3'-P inhibition. Noteworthy, present calculated RAL structures bound to free viral DNA resemble those found in RAL-intasome crystals, especially concerning the contacts between the fluorobenzyl group and the conserved 5'C(4)pA(3)3' step. We propose that RAL inhibits IN, in binding first unprocessed DNA. Similarly to anticancer drug poisons acting on topoisomerases, its interaction with DNA does not alter the cut, but blocks the subsequent joining reaction. We also speculate that INSTIs having viral DNA rather IN as main target could induce less resistance. |
| Databáze: | OpenAIRE |
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