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nucleoside reverse transcriptase inhibitors

Candidate: concept label1 source documents6 linked claims
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Aliases

NRTI, nucleoside RT inhibitors

Extracted Explainers

What the tool is doing

This review describes NRTIs as dideoxynucleosides that are converted intracellularly to ddNTP forms that inhibit HIV reverse transcriptase. Their antiviral action is tied to chain termination after incorporation.

Source 1DOIPubMed

Resources required

The drugs require host-cell kinase phosphorylation to become active triphosphates. Their activity and toxicity therefore depend on intracellular metabolism.

Source 1DOIPubMed

What problem it solves

They are used as effective antiretroviral agents and are described as a cornerstone of combination therapy. Some are also noted to have blood-brain barrier penetration associated with protection against AIDS dementia complex.

Source 1DOIPubMed

What it does not solve

The review emphasizes that they do not avoid host toxicity, because their triphosphates can also affect human DNA polymerases. Long-term treatment can produce cumulative mitochondrial dysfunction.

Source 1DOIPubMed

Alternatives

The review contrasts NRTIs with non-nucleoside RT inhibitors such as nevirapine, delavirdine, and efavirenz, and with nucleotide analogues such as adefovir.

Source 1DOIPubMed

Evidence Snippets

All currently used NRTI, such as ZDV, ddC, ddI, 3TC, D4T and abacavir, are dideoxynucleosides, which are phosphorylated intracellularly by host kinases to ddNTP.
Evidence 1Source 1DOIPubMedprovenance

Supporting Sources

Linked Claims

Claim 1class propertysupports1998Source 1DOIPubMed

NRTIs are described as effective antiretroviral drugs that reduce morbidity and mortality, especially in combination therapy.

Quoted textsource-backed
These drugs have demonstrated efficacy in reduction of morbidity and mortality, especially in combination therapy
Claim 2class propertysupports1998Source 1DOIPubMed

Some NRTIs are described as having blood-brain barrier penetration associated with protection against AIDS dementia complex.

Quoted textsource-backed
A special feature of some of these drugs is the protection against AIDS dementia complex, which appears to be related to good penetration of the blood–brain barrier
Claim 3compound class exceptionsupports1998Source 1DOIPubMed

Lamivudine is described as an exception among NRTIs because it is both an inhibitor of polymerase gamma and a substrate of its exonuclease activity, making incorporation less feasible.

Quoted textsource-backed
as an exception to the other NRTI, 3TC is both an inhibitor of the polymerase activity and a substrate of the integral 3′–5′ exonuclease activity of DNA polymerase γ, which makes incorporation less feasible
Claim 4mechanism summarysupports1998Source 1DOIPubMed

Because DNA polymerase gamma is the mitochondrial DNA replicase, inhibition of polymerase gamma by reverse transcriptase inhibitors can interfere with mitochondrial replication and function.

Quoted textsource-backed
since DNA polymerase γ is the only DNA polymerase involved in mitochondrial DNA (mtDNA) replication, the inhibitory action of NRTI on this enzyme can easily interfere in mitochondrial replication and function
Claim 5mechanism summarysupports1998Source 1DOIPubMed

NRTI triphosphates can inhibit human DNA polymerases beta and gamma in vitro, while polymerases alpha, delta, and epsilon are generally insensitive.

Quoted textsource-backed
in general, DNA polymerase α, δ and ε are insensitive to inhibition by ddNTP, but both DNA polymerases β and γ can be inhibited in vitro by these compounds
Claim 6mechanism summarysupports1998Source 1DOIPubMed

The review argues that many adverse effects of nucleoside reverse transcriptase inhibitors share a common mechanism of decreased mitochondrial energy-generating capacity.

Quoted textsource-backed
Behind most of these side-effects there appears to be a common mechanism: a decreased mitochondrial energy-generating capacity.