Antiretroviral potency of 4′-ethnyl-2′-fluoro-2′-deoxyadenosine, tenofovir alafenamide and second-generation NNRTIs across diverse HIV-1 subtypes

Njenda, Duncan; Aralaguppe, Shambhu G.; Singh, Kamalendra; Rao, Rohit; Sönnerborg, Anders; Sarafianos, Stefan G.; Neogi, Ujjwal

doi:10.1093/jac/dky256

Cited by 12 publications

(11 citation statements)

References 37 publications

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“…Subtype-specific differences in sensitivity and the impact of naturally occurring polymorphisms (PMs) are major emerging threats to the success of combination antiretroviral therapy (cART). In support of such subtype-specific differences, we recently reported that susceptibility to the non-nucleoside reverse transcriptase inhibitors rilpivirine and etravirine varies among subtypes [1]. Our real-life study also indicated subtype-specific differences in first-and second-line treatment failure with protease inhibitors [2].…”

supporting

confidence: 79%

Strain-specific effect on biphasic DNA binding by HIV-1 integrase

Hill

Rogers

Njenda

et al. 2019

Aids

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The oligomerization of HIV-1 integrase onto DNA is not well understood. Here we show that HIV-1 integrase binds the DNA in a biphasic (high-and low-affinity) modes. For HIV-1 subtype B, the high-affinity mode is ~100-fold greater than low-affinity mode (K d.DNA =37 and 3400 nM, respectively). The Kd.DNA values of patient-derived integrases containing subtype-specific polymorphisms were affected 2-4-fold, suggesting that polymorphisms may influence on effective-concentrations of inhibitors, since these inhibitors preferably bind to integrase-DNA complex.

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supporting

confidence: 79%

Strain-specific effect on biphasic DNA binding by HIV-1 integrase

Hill

Rogers

Njenda

et al. 2019

Aids

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“…In addition, when comparing intracellular dNTP/rNTP concentrations to polymerase kinetic parameters, it is important to note that variation in reported Km values can arise through discrepancies in (i) template features (DNA versus RNA, sequence, length, and structure), (ii) reaction conditions (buffer components, pH, presence of all dNTPs versus one dNTP), (iii) polymerase origins (viral strains, purification methods), and (iv) modes of the polymerizations (initiation vs. elongation). Similarly, when considering nucleotide/nucleoside inhibitor efficacy, IC50 data can vary depending on viral polymerase subtypes and physiological Mg 2+ concentrations (90,137). In addition to the steady state kinetic analyses, numerous structural and mechanistic investigations (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…While aptly poised for ATP-mediated excision, EFdA-TP is reincorporated into the DNA almost immediately upon excision by ATP (83). This novel drug is incorporated by HIV-1 RT with a Km of 0.024-.049 µM depending on template type-DNA versus RNA-and the subtype of HIV-1 RT used in the study (83,90). The Km associated with incorporation of EFdA-TP is lower than that of the natural substrate, dATP (0.06-0.10 µM) ( Table 1).…”

Section: Likementioning

confidence: 99%

Mechanistic cross-talk between DNA/RNA polymerase enzyme kinetics and nucleotide substrate availability in cells: Implications for polymerase inhibitor discovery

Coggins

Mahboubi

Schinazi

et al. 2020

Journal of Biological Chemistry

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Enzyme kinetic analysis reveals a dynamic relationship between enzymes and their substrates. Overall enzyme activity can be controlled by both protein expression and various cellular regulatory systems. Interestingly, the availability and concentrations of intracellular substrates can constantly change depending on conditions and cell types. Here, we review previously reported enzyme kinetic parameters of cellular and viral DNA and RNA polymerases with respect to cellular levels of their nucleotide substrates. This broad perspective exposes a remarkable co-evolution scenario of DNA polymerase enzyme kinetics with dNTP levels that can vastly change depending on cell proliferation profiles. Similarly, RNA polymerases display much higher Km values than DNA polymerases, possibly due to mM range rNTP concentrations found in cells (compared to µM range dNTP levels). Polymerases are commonly targeted by nucleotide analogue inhibitors for the treatments of various human diseases such as cancers and viral pathogens. Since these inhibitors compete against natural cellular nucleotides, efficacy of each inhibitor can be affected by varying cellular nucleotide levels in their target cells. Overall, both kinetic discrepancy between DNA and RNA polymerases and cellular concentration discrepancy between dNTPs and rNTPs present pharmacological and mechanistic considerations for therapeutic discovery.

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“…In vitro drug susceptibility assays showed that EFdA had significantly greater efficacy compared to other NRTIs [23]. Moreover, EFdA inhibits both WT and RTI-resistant viruses in a subtype-independent manner [25].…”

Section: La Antivirals Targeting Hiv-1 Rtmentioning

confidence: 99%

Long-Acting Anti-HIV Drugs Targeting HIV-1 Reverse Transcriptase and Integrase

2019

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One of the major factors contributing to HIV-1 drug resistance is suboptimal adherence to combination antiretroviral therapy (cART). Currently, recommended cART for HIV-1 treatment is a three-drug combination, whereas the pre-exposure prophylaxis (PrEP) regimens consist of one or two antivirals. Treatment regimens require adherence to a once or twice (in a subset of patients) daily dose. Long-acting formulations such as injections administered monthly could improve adherence and convenience, and thereby have potential to enhance the chances of expected outcomes, although long-lasting drug concentrations can also contribute to clinical issues like adverse events and development of drug resistance. Globally, two long-acting antivirals have been approved, and fifteen are in clinical trials. More than half of investigational long-acting antivirals target HIV-1 reverse transcriptase (HIV-1 RT) and/or integrase (HIV-1 IN). Here, we discuss the status and potential of long-acting inhibitors, including rilpivirine (RPV), dapivirine (DPV), and 4-ethynyl-2-fluoro-2-deoxyadenosine (EFdA; also known as MK-8591), which target RT, and cabotegravir (CAB), which targets IN. The outcomes of various clinical trials appear quite satisfactory, and the future of long-acting HIV-1 regimens appears bright.

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Antiretroviral potency of 4′-ethnyl-2′-fluoro-2′-deoxyadenosine, tenofovir alafenamide and second-generation NNRTIs across diverse HIV-1 subtypes

Abstract: Our combined virological and biochemical data suggest that EFdA inhibits both WT and reverse transcriptase inhibitor-resistant viruses efficiently in a subtype-independent manner. In contrast, HIV-1C is least susceptible to etravirine and rilpivirine.

Cited by 12 publications

References 37 publications

Strain-specific effect on biphasic DNA binding by HIV-1 integrase

Strain-specific effect on biphasic DNA binding by HIV-1 integrase

Mechanistic cross-talk between DNA/RNA polymerase enzyme kinetics and nucleotide substrate availability in cells: Implications for polymerase inhibitor discovery

Long-Acting Anti-HIV Drugs Targeting HIV-1 Reverse Transcriptase and Integrase

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