The HIV therapy market

Gubernick, Steven; Félix, Nuno Damácio de Carvalho; Lee, Dolim; Xu, Jing; Hamad, Bashar

doi:10.1038/nrd.2016.69

Cited by 19 publications

(22 citation statements)

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“…NRTIs are essential components of HAART and play a pivotal role in HIV treatment. NRTIs target the active site of the reverse transcriptase (RT) protein, a critical enzyme for the replication cycle of HIV, and they function as chain terminators of the viral DNA replication upon their incorporation in the DNA primer . However, several studies have linked the long‐term usage of the NRTIs to mitochondrial dysfunction and, additionally, several other studies have reported the correlation between mitochondrial toxicity, genomic instability, and the off‐target effect of NRTIs toward several human DNA polymerases (Pols) such as Pol γ .…”

Section: Introductionmentioning

confidence: 99%

“…NRTIs target the active site of the reverse transcriptase (RT) protein, a critical enzyme for the replication cycle of HIV, and they function as chain terminators of the viral DNA replication upon their incorporation in the DNA primer. 1 However, several studies have linked the longterm usage of the NRTIs to mitochondrial dysfunction 2,3 and, F I G U R E 1 Chemical structures of 2 0 -deoxycytidine-5 0triphosphate (dCTP); thymidine-5 0 -triphosphate (TTP); D-2 0 ,3 0dideoxycytidine-5 0 -triphosphate (D-ddCTP); L-2 0 ,3 0dideoxycytidine triphosphate (L-ddCTP); d4T-TP, (−)FTC-TP, and (−)3TC-TP are the triphosphate forms of stavudine d4T, emtricitabine, (−)FTC, and lamivudine, (−)3TC, respectively. (+)FTC-TP is the enantiomer of (−)FTC-TP additionally, several other studies have reported the correlation between mitochondrial toxicity, genomic instability, and the off-target effect of NRTIs toward several human DNA polymerases (Pols) such as Pol γ.…”

Section: Introductionmentioning

confidence: 99%

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Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine

et al. 2019

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The retrovirus HIV‐1 has been a major health issue since its discovery in the early 80s. In 2017, over 37 million people were infected with HIV‐1, of which 1.8 million were new infections that year. Currently, the most successful treatment regimen is the highly active antiretroviral therapy (HAART), which consists of a combination of three to four of the current 26 FDA‐approved HIV‐1 drugs. Half of these drugs target the reverse transcriptase (RT) enzyme that is essential for viral replication. One class of RT inhibitors is nucleoside reverse transcriptase inhibitors (NRTIs), a crucial component of the HAART. Once incorporated into DNA, NRTIs function as a chain terminator to stop viral DNA replication. Unfortunately, treatment with NRTIs is sometimes linked to toxicity caused by off‐target side effects. NRTIs may also target the replicative human mitochondrial DNA polymerase (Pol γ), causing long‐term severe drug toxicity. The goal of this work is to understand the discrimination mechanism of different NRTI analogues by RT. Crystal structures and kinetic experiments are essential for the rational design of new molecules that are able to bind selectively to RT and not Pol γ. Structural comparison of NRTI‐binding modes with both RT and Pol γ enzymes highlights key amino acids that are responsible for the difference in affinity of these drugs to their targets. Therefore, the long‐term goal of this research is to develop safer, next generation therapeutics that can overcome off‐target toxicity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine

et al. 2019

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“…Approximately 36.9 million people worldwide are living with HIV, and approximately 2 million people were newly infected in 2014 (Gubernick et al, 2016). Despite considerable efforts, no effective regimen to eliminate the virus is currently available.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of F18, a Derivative of Calanolide A, in Human Liver Microsomes and Cytosol

Zhang

Guo

et al. 2017

Front. Pharmacol.

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10-Chloromethyl-11-demethyl-12-oxo-calanolide (F18), an analog of calanolide A, is a novel potent nonnucleoside reverse transcriptase inhibitor against HIV-1. Here, we report the metabolic profile and the results of associated biochemical studies of F18 in vitro and in vivo. The metabolites of F18 were identified based on liquid chromatography-electrospray ionization mass spectrometry and/or nuclear magnetic resonance. Twenty-three metabolites of F18 were observed in liver microsomes in vitro. The metabolism of F18 involved 4-propyl chain oxidation, 10-chloromethyl oxidative dechlorination and 12-carbonyl reduction. Three metabolites (M1, M3-1, and M3-2) were also found in rat blood after oral administration of F18 and the reduction metabolites M3-1 and M3-2 were found to exhibit high potency for the inhibition of HIV-1 in vitro. The oxidative metabolism of F18 was mainly catalyzed by cytochrome P450 3A4 in human microsomes, whereas flavin-containing monooxygenases and 11β-hydroxysteroid dehydrogenase were found to be involved in its carbonyl reduction. In human cytosol, multiple carbonyl reductases, including aldo-keto reductase 1C, short-chain dehydrogenases/reductases and quinone oxidoreductase 1, were demonstrated to be responsible for F18 carbonyl reduction. In conclusion, the in vitro metabolism of F18 involves multiple drug metabolizing enzymes, and several metabolites exhibited anti-HIV-1 activities. Notably, the described results provide the first demonstration of the capability of FMOs for carbonyl reduction.

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“…HIV | reverse transcriptase | covalent inhibitors | X-ray crystallography | mass spectrometry H IV-1 reverse transcriptase (RT) has been the primary molecular target for anti-HIV chemotherapy (1). This is reflected in the success of the once-a-day medications Atripla and Complera, which consist of two nucleoside RT inhibitors (NRTIs), emtricitabine and tenofovir, and one nonnucleoside RT inhibitor (NNRTI), either efavirenz or rilpivirine (2) (Fig.…”

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confidence: 99%

“…For NNRTIs, the most common resistance mutations are Lys103Asn (K103N) and Tyr181Cys (Y181C), which are observed in 57% and 25% of patients failing NNRTI treatment (4). Y181C has been a major hurdle in the development of NNRTIs (1,5,6); it is debilitating for many NNRTIs, including the first approved drug in this class, nevirapine. Nevertheless, nevirapine remains on the WHO's Model List of Essential Medicines and it is used in the developing world as a monotherapy to prevent mother-to-child viral transmission.…”

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confidence: 99%

Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography

Chan

Lee

Spasov

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Development of resistance remains a major challenge for drugs to treat HIV-1 infections, including those targeting the essential viral polymerase, HIV-1 reverse transcriptase (RT). Resistance associated with the Tyr181Cys mutation in HIV-1 RT has been a key roadblock in the discovery of nonnucleoside RT inhibitors (NNRTIs). It is the principal point mutation that arises from treatment of HIV-infected patients with nevirapine, the first-in-class drug still widely used, especially in developing countries. We report covalent inhibitors of Tyr181Cys RT (CRTIs) that can completely knock out activity of the resistant mutant and of the particularly challenging Lys103Asn/Tyr181Cys variant. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme inhibition kinetics, mass spectrometry, protein crystallography, and antiviral activity in infected human T-cell assays. The CRTIs are also shown to be selective for Cys181 and have lower cytotoxicity than the approved NNRTI drugs efavirenz and rilpivirine.

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The HIV therapy market

Cited by 19 publications

References 0 publications

Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine

Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine

Metabolism of F18, a Derivative of Calanolide A, in Human Liver Microsomes and Cytosol

Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography

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