Medical Pharmacology Chapter 36:  Antiviral Drugs

Integrate Strand Transfer Inhibitors

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Integrase Strand Transfer Inhibitors (INSTI):

    • Sites of Antiretroviral Drug Actions¹⁰

      a: The lifecycle of HIV-1, showing the step at which enfuvirtide acts, and also the steps targeted by other drugs.160 b:  "Simplified schematic of the mechanism by which enfuvirtide inhibits viral entry into host cells.10    The envelope glycoprotein of HIV-1 consists of two non-covalently associated subunits, gp120 and gp41. After attachment of HIV-1 to its target cells carrying the CD4 receptor, gp120 interacts with the CD4 receptor, which initiates a series of conformational changes in gp41 and gp120 that lead to the insertion of a region of gp41 into the membrane of the host cell, and formation of a ' pre-hairpin intermediate' (top). Further changes in the confirmation of gp41 bring the viral and cellular membranes into close enough proximity for membrane fusion (bottom left). Abbreviations: NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor" Attribution:  Slight modification of Figure 1 from:  LaBonte J Lebbos J Kirkpatrick nature Reviews Drug Discovery 2, 345-346 (May 2003).10

    • Integrase strand inhibitors include:

      • Dolutegravir (Tivicay)

        • Dolutegravir (Tivicay)

      • Elvitegravir (Vitekta)

      • Raltegravir (Isentress)

    • There are currently five recommended protocols for antiretroviral treatment (ART)-naïve individuals.⁹  

      • Four of the five approaches are based on integrase strand transfer inhibitors (INSTIs) with the fifth utilizing a ritonavir-boosted protease inhibitor-based protocol.

        • Alternative or "other" protocols remain available.⁹

    • Integrase strand transfer inhibitors (INSTIs) block an enzyme, integrase, required for replication of HIV-1 in HIV-2.⁷ 

      •  

        "The Discovery and Development of Inhibitors of HIV-1 Integrase"¹²

        Huzuda D and the Merck Integrase Inhibitor Team The Discover and Development of Inhibitors of HIV-1 Integrase  https://www.youtube.com/watch?v=HZBEq8ZBR4g, (12/2009) UC Berkeley Events YouTube Channel:  https://www.youtube.com/channel/UCFkid-1EIBbauJLbMFDp2Cg

      • Interaction of integrase inhibitor drugs with reverse-transcribed HIV-DNA prevents provirus integration into host cell chromosomes.⁷   

        • Specifically, HIV integrase inhibitors prevent covalent bond formation between host and viral DNA, a process that defines "strand transfer." ¹

          • Following covalent bond formation which joins host DNA and viral DNA, cellular repair processes "seal" the viral DNA in the chromosome.^11,1

            • HIV-1 Integrase Mechanism of Strand Transfer and Site of

              Raltegravir Blockade¹¹

              Attribution:  This figure above corresponds to Figure 1 (with a slight modification) from reference 11 (Hicks C Gulick RM Raltegravir:  The First HIV Type 1 Integrase Inhibitor. Clin Infect Disease Apr. 1; 48(7):  931-939 2009, http://www-ncbi-nlm-nih-gov.proxy.kumc.edu:2048/pubmed/19231980) Abbreviations: LTR:  Long Terminal Repeats PIC:  Preintegration Complex

          • The mechanism of inhibitor action may be due to interactions between the drug and divalent cations associated with integrase catalytic site. ¹

            •  

              Interaction of Integrase Inhibitors and Catalytic Site Cations14

              Hopur:  "Structure active relationship of elvitegravir and raltegravir.  Benzyl group in a hydrophobic pocket and a triad to chelate the two Mg2+ ions." https://commons.wikimedia.org/wiki/File:SAR_of_elvitegravir_and_raltegravir.png

        • Approximately 40-100 integrase enzyme molecules are contained within each HIV viral particle.¹³ 

          • The central role of integrase, as noted earlier, is to facilitate insertion of viral cDNA (complementary [to the RNA sequence] DNA) into infected cell genomes.

            • Another activity of integrase may be its role as a reverse transcription cofactor.¹³   

          • Ultimately for production of viral proteins, complete integration of viral cDNA into a chromosome is required.¹³   

            • After reverse transcriptase mediates RNA to DNA transcription, viral cDNA is modified by integrase through trimming of the 3'-ends of viral DNA (also known as 3'-processing).

              • This processing step requires both intact integrase and integrity of the last 10-20 base pairs at each end of the viral cDNA. 3' processing involves endonucleolytic cleavage of the 3'-ends of viral DNA.

              • Normally, this step results in a CA-3'-hydroxyl DNA,  constituting reactive intermediates needed for strand transfer.

              • After 3'-processing, the integrase enzyme remains associated with viral cDNA resulting in a complex, bridging both ends of viral DNA within intracellular components described as "pre-integration complexes" (PICs). PICs contain not only integrase-DNA complexes but also viral proteins including reverse transcriptase, matrix, nucleocapsid andVpr which facilitate PICs transport through the nuclear envelope.¹³ 

                •  In the nucleus integrase catalyzes viral cDNA insertion into host chromosomes.

                  • This "strand transfer" reaction involves ligation of the viral 3'-0H DNA ends to the host cell 5'-DNA phosphate.

                  • The final step of integration necessitates 5'-end ligation of the viral DNA which occurs following both removal of the last to nucleotides at the proviral DNA 5' ends and gap filling (extension) from the 3'-0H and of genomic DNA. ¹³ 

          • The reader is directed to reference 13 for further details of this complex process.

    • Adverse Effects:

      • As an antiretroviral class, side effects associated with integrase strand transfer inhibitors (INSTIs) tend to be less severe than side effects associated with drugs belonging to other antiretroviral groups.⁷  

        • The most frequently described adverse events include headache and gastrointestinal effects.

          • Some nervous system, including neuropsychiatric, adverse effects  are noted less frequently and appear milder, when compared to efavirenz and protease inhibitors.

        • Side effects considered both rare and severe include rhabdomyolysis and systemic hypersensitivity responses.⁷