Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs

Smith, Steven J.; Zhao, Xue Zhi; Passos, Dario Oliveira; Lyumkis, Dmitry; Burke, Terrence R.; Hughes, Stephen H.

doi:10.3390/v13020205

Cited by 47 publications

(77 citation statements)

References 158 publications

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“…MMPs are part of a family of structurally related Zn ++ -dependent endopeptidases [39]. As DTG possesses a prominent MBP for binding to the metal ions [14], we hypothesized that DTG inhibits activity of MMP by binding to Zn ++ at the catalytic domain. Since DTG inhibits MMP-2, 8, 9, 14, and 19 to a higher extent (low IC 50 values, Fig.…”

Section: Dtg Binds To Zn ++ At Catalytic Domain Of Mmp To Inhibit the Enzyme's Activitymentioning

confidence: 99%

“…DTG is an integrase strand transfer inhibitor (INSTI) that blocks the action of the viral integrase enzyme, which is responsible for the insertion of the viral genome into the host cellular DNA. It possesses a metal-binding pharmacophore (MBP, also referred as a metal-binding group, MBG) for engagement with active metal ion (Mg ++ ) sites in the HIV-1 integrase [14]. With a metal chelating motif in the chemical structure, DTG possesses potential to interact with other metalloenzymes that are critical for normal biological activities, including cell proliferation, differentiation, signaling, nucleic acid modification, and protein degradation.…”

Section: Introductionmentioning

confidence: 99%

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Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

et al. 2021

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Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn++ at the enzyme’s catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment.

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Section: Dtg Binds To Zn ++ At Catalytic Domain Of Mmp To Inhibit the Enzyme's Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

et al. 2021

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“…We have a detailed understanding of the atomic-level organization of mature processed forms for both the HIV-1 structural proteins (MA, CA, NC) and the enzymes (PR, RT, IN), including wildtype and drug-resistant variants, and we have a good understanding of how they interact with other proteins, nucleic acid substrates, and inhibitors. These structures have helped in the development of antiretroviral drugs [17][18][19] . There is also useful information about the structures of the Gag polyprotein and the immature virion [20][21][22][23][24][25] .…”

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confidence: 99%

Cryo-EM Structure of the Pol Polyprotein Provides Insights into HIV Maturation

Harrison

Passos

Bruhn

et al. 2021

Preprint

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Many retroviral proteins are initially translated from unspliced full-length RNA as polyprotein precursors that are subsequently processed by the viral protease (PR) to yield the mature forms. In HIV-1, the enzymes, PR, reverse transcriptase (RT), and integrase (IN), are produced as part of the Gag-Pol polyprotein. While structures of the mature proteins have aided our understanding of catalytic mechanisms and the design of antiretroviral drugs, knowledge of the architecture and functional implications of the immature forms prior to PR-mediated cleavage is limited. We developed a system to produce and purify the HIV-1 Pol polyprotein intermediate precursor and determined its high-resolution cryo-EM structure. The RT portion of the polyprotein has an architecture similar to the mature RT p66/p51 heterodimer, and dimerization of the RT portion draws together two PR monomers to activate proteolytic processing. HIV-1 thus may leverage the dimerization interfaces in Pol to regulate the assembly and maturation of the polyprotein precursors.

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“…BIC and DTG retain high potencies against resistant mutants that arise in response to the first generation INSTIs raltegravir (RAL) and elvitegravir (EVG) [2][3][4][5][6][7]. When compared to RAL and EVG, the resistance profiles of DTG and BIC are much more favorable [8,9]. Only a few DTG-and BIC-resistant mutants have been identified either in selection studies in vitro or in HIVinfected individuals who are treatment-experienced [2,3,10,11].…”

Section: Introductionmentioning

confidence: 99%

INSTIs and NNRTIs Potently Inhibit HIV-1 Polypurine Tract Mutants in a Single Round Infection Assay

Smith

Ferris

Zhao

et al. 2021

Viruses

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Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral compounds that prevent the insertion of a DNA copy of the viral genome into the host genome by targeting the viral enzyme integrase (IN). Dolutegravir (DTG) is a leading INSTI that is given, usually in combination with nucleoside reverse transcriptase inhibitors (NRTIs), to treat HIV-1 infections. The emergence of resistance to DTG and other leading INSTIs is rare. However, there are recent reports suggesting that drug resistance mutations can occur at positions outside the integrase gene either in the HIV-1 polypurine tract (PPT) or in the envelope gene (env). Here, we used single round infectivity assays to measure the antiviral potencies of several FDA-approved INSTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) against a panel of HIV-1 PPT mutants. We also tested several of our promising INSTIs and NNRTIs in these assays. No measurable loss in potency was observed for either INSTIs or NNRTIs against the HIV-1 PPT mutants. This suggests that HIV-1 PPT mutants are not able, by themselves, to confer resistance to INSTIs or NNRTIs.

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Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs

Cited by 47 publications

References 158 publications

Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

Cryo-EM Structure of the Pol Polyprotein Provides Insights into HIV Maturation

INSTIs and NNRTIs Potently Inhibit HIV-1 Polypurine Tract Mutants in a Single Round Infection Assay

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