Limits...
Inhibiting the HIV integration process: past, present, and the future.

Di Santo R - J. Med. Chem. (2013)

Bottom Line: The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported.The role played by the resistance is elucidated, as well as the possibility of bypassing this problem.New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur, Fondazione Cenci Bolognetti, "Sapienza" Università di Roma , P.le Aldo Moro 5, I-00185 Rome, Italy.

ABSTRACT
HIV integrase (IN) catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. The discovery of raltegravir validated the existence of the IN, which is a new target in the field of anti-HIV drug research. The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported. The role played by the resistance is elucidated, as well as the possibility of bypassing this problem. New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.

Show MeSH
ST step. The attack of the 3′ ends of vDNA on the phosphodiesterbonds of host DNA is coordinated by metal ions.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3926363&req=5

fig4: ST step. The attack of the 3′ ends of vDNA on the phosphodiesterbonds of host DNA is coordinated by metal ions.

Mentions: The exposed CA-3′-OH DNA ends are then ready for thesecondcatalytic step, ST. This reaction occurs via divalent metal-mediatedphosphodiester transesterification, which utilizes the two 3′-OHgroups on the vDNA as nucleophiles.44 Accordingto this mechanism, the two viral 3′-OH groups exposed by the3′-P step attack phosphodiester bonds on complementary strandsof the host DNA. The metal ion cofactors play a dual role during catalysis;they help stabilize the enzyme–DNA complex and facilitate thecharge flow from the viral 3′-OH to the departing 3′-OHof the host DNA.48 In this mechanism, MA and MB are capable of interacting with the scissilephosphate in a highly structured SN2-like mechanism. Particularly,metal ion A acts as a Lewis acid to facilitate the function of thenucleophile, which is properly oriented with the help of the proteinside chain, and metal B activates the 3′-oxoanion leaving groupand stabilizes the pentacoordinate transition state (Figure 4).42,43a,49,50 Therefore, the 5′ end of the hostDNA acts as the leaving group of the intermediate, completing theST reaction. After this ST step, the resulting DNA gaps between theproviral and host DNA are filled in by host cell’s DNA polymerases(Figure 3).51


Inhibiting the HIV integration process: past, present, and the future.

Di Santo R - J. Med. Chem. (2013)

ST step. The attack of the 3′ ends of vDNA on the phosphodiesterbonds of host DNA is coordinated by metal ions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926363&req=5

fig4: ST step. The attack of the 3′ ends of vDNA on the phosphodiesterbonds of host DNA is coordinated by metal ions.
Mentions: The exposed CA-3′-OH DNA ends are then ready for thesecondcatalytic step, ST. This reaction occurs via divalent metal-mediatedphosphodiester transesterification, which utilizes the two 3′-OHgroups on the vDNA as nucleophiles.44 Accordingto this mechanism, the two viral 3′-OH groups exposed by the3′-P step attack phosphodiester bonds on complementary strandsof the host DNA. The metal ion cofactors play a dual role during catalysis;they help stabilize the enzyme–DNA complex and facilitate thecharge flow from the viral 3′-OH to the departing 3′-OHof the host DNA.48 In this mechanism, MA and MB are capable of interacting with the scissilephosphate in a highly structured SN2-like mechanism. Particularly,metal ion A acts as a Lewis acid to facilitate the function of thenucleophile, which is properly oriented with the help of the proteinside chain, and metal B activates the 3′-oxoanion leaving groupand stabilizes the pentacoordinate transition state (Figure 4).42,43a,49,50 Therefore, the 5′ end of the hostDNA acts as the leaving group of the intermediate, completing theST reaction. After this ST step, the resulting DNA gaps between theproviral and host DNA are filled in by host cell’s DNA polymerases(Figure 3).51

Bottom Line: The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported.The role played by the resistance is elucidated, as well as the possibility of bypassing this problem.New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur, Fondazione Cenci Bolognetti, "Sapienza" Università di Roma , P.le Aldo Moro 5, I-00185 Rome, Italy.

ABSTRACT
HIV integrase (IN) catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. The discovery of raltegravir validated the existence of the IN, which is a new target in the field of anti-HIV drug research. The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported. The role played by the resistance is elucidated, as well as the possibility of bypassing this problem. New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.

Show MeSH