Viral Life Cycle and Integration Reaction Mechanism

 Home Page National Cancer Institute Macromolecular Crystallography Laboratory Retroviral Integrase Project NCI-Frederick MCL - Protein Structure Section
Structures determined by the Macromolecular Crystallography Laboratory, Protein Structure Section at the NCI-Frederick campus. Work performed in collaboration with the Skalka Laboratory in the Institute for Cancer Research, Fox Chase Cancer Center.





Various steps in the retroviral life cycle and the three retroviral enzymes.

(1) Protease enables the viral particle to form within the cell. After the virus exits the cell, this enzyme causes the "immature" particle to become an infectious virus. Drugs designed against HIV-1 PR are in common use.
(2) Reverse Transcriptase copies the viral genome, composed of RNA, to a form that can enter the cell nucleus, become part of the host cell genes, and take over the cell. Drugs designed against HIV-1 RT are now in clinical trials.
(3) Integrase processes the reverse-transcribed (copied) viral DNA and splices it into the host genes. There are no drugs against IN. Many laboratories, including ours, are in the earliest stages of developing anti-IN compounds. We have solved the first crystal structure of any anti-IN inhibitor bound to Integrase.

Note: These inhibitors are not drugs and they are highly toxic. Significant further research must be done in order to increase solubility, increase potency, and reduce toxicity before any chemicals can be considered for human testing or medical use. Many thousands of inhibitors are tested for every one that passes the stringent tests required before an inhibitor can be used as a drug.


IN processing reaction



IN joining reaction


This last part, the integration reaction, may be the key to the early interest in avian sarcoma virus. Sarcoma means cancer, and the earliest virus researchers, including Dr. Peyton Rous, were interested in how a virus can cause cancer. Viruses are not very selective about where IN inserts viral DNA into the cell genes. If viral DNA is inserted into a critical DNA sequence that codes for a cell life cycle regulatory protein, the protein may no longer work. This disruption of a key protein can kill the cell or cause it to continue growing and dividing without control. These "immortal" cells can form sarcomas- cancers. ASV is more than a virus related to HIV- it is a tool to study cancer.

Click here for more information about the Y-3 inhibitor of ASV IN.

For more information on integrases, visit our collaborators' web site at the Skalka Laboratory.

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If you have questions or comments about the Integrase Project web site,
contact: Jerry N. Alexandratos at alexandr@ncifcrf.gov.