Structural Biology of HIV Integrase Strand Transfer Inhibitors

Jozwik, I.K.; Passos, Dario Oliveira; Lyumkis, Dmitry

doi:10.1016/j.tips.2020.06.003

Cited by 34 publications

(32 citation statements)

References 90 publications

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“…The available structures of the INSTIs in the active sites of HIV-1, SIV rcm , and PFV intasomes can be used as models to propose explanations for the effects of INSTI-resistant mutations on the susceptibilities of the second-generation INSTIs [ 26 , 27 ]. Those who are interested in this problem can consult the two recent reviews that are focused on how changes in the structures of HIV-1/SIV rcm intasomes caused by mutations in IN affect the potencies of the INSTIs [ 139 , 140 ]. The mutations in the drug-resistant viral variants found in populations of treated individuals can be mapped onto the active sites of IN.…”

Section: Using Structural Analyses To Understand the Mechanism(s) mentioning

confidence: 99%

“…Because the G140/Q148 mutants are broadly associated with resistance to the available INSTIs, we will briefly consider what is believed to be the underlying mechanism. There is an important interaction between a particular bound water molecule, behind the active site, the catalytic residues D116 and E152, and the nearby residue Q148 [ 26 , 27 , 140 ]. If the amino acid at position 148 is replaced (Q148H/K/R), the bound water molecule is expelled, which means that this key interaction is also lost.…”

Section: Using Structural Analyses To Understand the Mechanism(s) mentioning

confidence: 99%

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Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs

Smith

Zhao

Passos

et al. 2021

Viruses

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Integrase strand transfer inhibitors (INSTIs) are currently recommended for the first line treatment of human immunodeficiency virus type one (HIV-1) infection. The first-generation INSTIs are effective but can select for resistant viruses. Recent advances have led to several potent second-generation INSTIs that are effective against both wild-type (WT) HIV-1 integrase and many of the first-generation INSTI-resistant mutants. The emergence of resistance to these new second-generation INSTIs has been minimal, which has resulted in alternative treatment strategies for HIV-1 patients. Moreover, because of their high antiviral potencies and, in some cases, their bioavailability profiles, INSTIs will probably have prominent roles in pre-exposure prophylaxis (PrEP). Herein, we review the current state of the clinically relevant INSTIs and discuss the future outlook for this class of antiretrovirals.

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Section: Using Structural Analyses To Understand the Mechanism(s) mentioning

confidence: 99%

Section: Using Structural Analyses To Understand the Mechanism(s) mentioning

confidence: 99%

Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs

Smith

Zhao

Passos

et al. 2021

Viruses

Self Cite

View full text Add to dashboard Cite

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“…These drugs bind to the active site of the IN CCD, displacing the reactive 3' end of the viral DNA and preventing its insertion into the host DNA [73]. Mutations in the IN active site confer resistance to INSTIs by directly or indirectly inhibiting drug binding, albeit at a viral fitness cost (reviewed in [15,108,109]). As such, other compensatory mutations that increase the catalytic activity of IN are additionally found in patients undergoing INSTI therapy [108,109].…”

Section: The Essential Catalytic Function Of Integrasementioning

confidence: 99%

“…Mutations in the IN active site confer resistance to INSTIs by directly or indirectly inhibiting drug binding, albeit at a viral fitness cost (reviewed in [15,108,109]). As such, other compensatory mutations that increase the catalytic activity of IN are additionally found in patients undergoing INSTI therapy [108,109]. Emergence of resistance and cross-resistance is commonly observed for the two first-generation INSTIs, raltegravir and elvitegravir [110].…”

Section: The Essential Catalytic Function Of Integrasementioning

confidence: 99%

“…Emergence of resistance and cross-resistance is commonly observed for the two first-generation INSTIs, raltegravir and elvitegravir [110]. In spite of the improved potency and higher barriers for resistance, second-generation inhibitors also select for viral resistance [108,111], highlighting the need for antiretroviral compounds that inhibit IN by a different mode of action.…”

Section: The Essential Catalytic Function Of Integrasementioning

confidence: 99%

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Going beyond Integration: The Emerging Role of HIV-1 Integrase in Virion Morphogenesis

Elliott

Kutluay

2020

Viruses

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The HIV-1 integrase enzyme (IN) plays a critical role in the viral life cycle by integrating the reverse-transcribed viral DNA into the host chromosome. This function of IN has been well studied, and the knowledge gained has informed the design of small molecule inhibitors that now form key components of antiretroviral therapy regimens. Recent discoveries unveiled that IN has an under-studied yet equally vital second function in human immunodeficiency virus type 1 (HIV-1) replication. This involves IN binding to the viral RNA genome in virions, which is necessary for proper virion maturation and morphogenesis. Inhibition of IN binding to the viral RNA genome results in mislocalization of the viral genome inside the virus particle, and its premature exposure and degradation in target cells. The roles of IN in integration and virion morphogenesis share a number of common elements, including interaction with viral nucleic acids and assembly of higher-order IN multimers. Herein we describe these two functions of IN within the context of the HIV-1 life cycle, how IN binding to the viral genome is coordinated by the major structural protein, Gag, and discuss the value of targeting the second role of IN in virion morphogenesis.

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Latest Progress on Tuberculosis and HIV Co‐Infection: A Closer Look at People of Different Ages

Yusuf Aliyu,

Adeleke

2024

Advanced Therapeutics

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Tuberculosis (TB) and Human Immunodeficiency virus (HIV) coinfection continues to be a very serious health concern globally. Even though TB is treatable, it remains among the leading cause of death especially among HIV‐infected individuals. Although the emergence of antiretroviral therapy (ART) has positively impacted the treatment of HIV, it is a major risk factor for developing active TB disease. The treatment of HIV and TB coinfection is associated with many challenges, one of which is the requirement of treatment with multiple medications for an extended period which is faced by all infected individuals across every age group, however, some of the challenges are peculiar to a specific age range. This review provides a comprehensive analysis of HIV and TB co‐infection among persons within different age brackets and the characteristics of both diseases, their current treatment guidelines, the challenges they pose, and their impact on global health are examined and reported herein.

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Structural Biology of HIV Integrase Strand Transfer Inhibitors

Cited by 34 publications

References 90 publications

Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs

Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs

Going beyond Integration: The Emerging Role of HIV-1 Integrase in Virion Morphogenesis

Latest Progress on Tuberculosis and HIV Co‐Infection: A Closer Look at People of Different Ages

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