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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5613_Библиотеки_им_академика_М_И_Перельмана
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________________________________________________________________________________
Doravirine (Pifeltro): A Third-Generation
Non-Nucleoside Reverse Transcriptase
Inhibitor as a Treatment of HIV-1 Infection
Jie Jack Li
The coronavirus pandemic has wreaked havoc around the globe during the last few years.
Yet, we must not forget that an epidemic has been going on for decades, i.e., the
HIV/AIDS epidemic. From the beginning of the 1980s, AIDS is estimated to have killed
more than 25 million worldwide. According to the United Nations’ statistics, nearly 40
million people were living with HIV in 2021.
tuberculosis
sees about 40,000 new infections annually.
The FDA’s approval of doravirine (Pifeltro, 1), a third-generation non-
nucleoside reverse transcriptase inhibitor (NNRTI), in 2018 was timely to contribute to
the WHO’s lofty goal of stopping the HIV/AIDS pandemic by 2030.
Chemistry and Pharmacology of Drug Discovery, First Edition. Edited by Jie Jack Li.
© 2025 John Wiley & Sons, Inc. Published 2025 by John Wiley & Sons, Inc.
as the world’s deadliest infectious disease. Even today, the United States
1
Notably, AIDS has replaced malaria and
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Chemistry and Pharmacology of Drug Discovery
1. Background
Françoise Barré-Sinoussi and Luc Montagnier in France discovered the human
immunodeficiency virus (HIV, Figure
2008. The HIV encodes 15 proteins although only three of them have enzymatic
activities: reverse transcriptase, protease and integrase. Nevertheless, even many
nonenzymatic proteins have been successfully targeted as treatments of HIV/AIDS.
1) in 1983 and were bestowed the Nobel Prize in
Figure 1. The structure of the HIV
Since the discovery of AZT (azidothymidine, Retrovir, 2) as the first effective
treatment of AIDS, seven additional HIV-1 nucleoside reverse transcriptase inhibitors
(NRTIs)
Epivir, 3) and Gilead’s tenofovir disoproxil (Viread, 4) and emtricitabine (FTC, Emtriva,
5), respectively. TNRTIs are orthosteric inhibitors binding to the active site (DNA
have been approved by the FDA. They include GSK’s Lamivudine (3TC,
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Chapter 2. Doravirine (Pifeltro)
polymerase) of the reverse transcriptase (vide infra), a key viral enzyme that produces
double-stranded viral DNA genomes from a single-stranded viral RNA genome. In short,
NRTIs function as viral DNA chain terminators.
2
NRTIs have become the workhorse of highly active antiretroviral therapy
(HAART), also known as
antiretroviral therapy (ART): cocktail HIV-1 drugs that have
significantly contributed to transforming AIDS from a death sentence to a chronic
infection that can be managed with medicine.
HIV protease inhibitors were among the earliest drugs specifically developed for
treating AIDS (AZT was initially developed as a cancer drug in the 1960s). Ten HIV
protease inhibitors are on the market including ritonavir (Norvir, 1996), fosamprenavir
(2005) and darunavir (Prezista, 2006). They are peptidomimetics that work as “transition
state mimics.” Their key hydroxyl group mimics the tetrahedral transition state of an
amide bond of the polyprotein substrate being hydrolyzed by HIV protease.
3
There are also four HIV integrase inhibitors approved by the FDA. They include
raltegravir (Isentress, 2007), dolutegravir (Trivicay, 2013), elvitegravir (Vitekta, 2014),
and bictegravir (Biktarvy with emtricitabine–tenofovir alafenamide, 2018). They work as
integrase strand transfer inhibitors (InSTIs) to block the viral DNA from transferring its
strand onto host DNA. All four HIV integrase inhibitors possess a very polar warhead as
a bioisostere of diketoacid to chelate to the two magnesium ions that are important to
4
integrase’s catalytic activities.
Furthermore, HIV entry inhibitors encompasses several targets. One is HIV
fusion inhibitor enfuvirtide (Fuzeon) by Roche, approved in 2003. The other is CCR5
antagonist maraviroc (Selzentry) by Pfizer, approved in 2007. BMS’s attachment
5
inhibitor, fostemsavir (Rukobia) became available in 2020.
More excitingly, long-acting HIV drugs are now available, which greatly
enhance patience compliance. Among them, one is ViiV’s Cabenuva, given one injection
per month, combining an HIV integrase inhibitor cabotegravir (6) and a non-NRTI
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rilpivirine (Edurant, 7).6 Gilead’s HIV-1 capsid protein inhibitor, lenacapavir (Sunlenca,
8), only needs to be given as two injections per year!7
Today, more than 30 approved drugs can efficiently suppress HIV viral load
below the detectable level. Sadly, there is no effective vaccine, and no cure is available
today to eradicate HIV infections globally.
Chemistry and Pharmacology of Drug Discovery
2. Pharmacology
HIV-1 reverse transcriptase is the primary enzyme responsible for the conversion of the
viral single strand RNA to the double strand DNA.
In the late 1950s, Francis Crick, the codiscoverer of the double helix structure,
advanced the central dogma in molecular biology. Central dogma states that the genetic
information flows in a two-step process of transcription and translation in a unidirectional
vector: DNA → mRNA → Protein (Figure
2). mRNA stands for messenger ribonucleic
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acid. Here comes a question. How does a retrovirus, such as HIV duplicate itself?
Howard Temin and David Baltimore discovered reverse transcriptase in 1970 and won
the Nobel Prize in 1975.
HIV reverse transcriptase enzyme is a component of the virion and is encoded
by the pol gene and is manufactured in the HIV-infected cells as a gag-pol fusion
polyprotein. HIV reverse transcriptase is an RNA-dependent DNA polymerase (RdDp).
But it is not the only enzyme necessary for the translation of RNA to DNA. The other
enzymes for this conversion also include DNA-dependent DNA polymerase (DdDp) and
ribonuclease (RNase) H (see Figure
transcriptase, the p51 subunit does not have a catalytic function; it only participates in
conformational regulation for the p66 subunit. The p66 subunit, which is responsible for
performing all catalytic activities, consists of the DNA polymerase domain and the
RNase H domain.
NRTIs as represented by 3–5 are competitive (with ATP) inhibitors. The reverse
transcriptase’s DNA polymerase activity
transcriptase inhibitors. They are prodrugs that are converted to the corresponding
nucleotides via phosphorylated by the host cellular kinases. From nucleosides 2–5, the
corresponding nucleotides generated by cellular kinases bind to the active site of the
DNA polymerase and compete with their natural counterparts thus prevent insertion of
the next endogenous nucleotide. Because the artificial nucleotides do not have a 3′-OH in
the ribose ring, they act as chain terminators and block DNA polymerization after being
incorporated into a growing strand of the pro-viral DNA during reverse transcription. The
active site locates at the palm region, where DNA is elongated, as the polymerase shapes
like a human right hand, so the four constituent subdomains are referred to as fingers,
palm, thumb, and connection (Figure
HIV-1 reverse transcriptase enzyme is extremely error-prone with a high error
rate (1 in 1700 bases), which produces higher incidents of mutation. As shown in Figure
8
Chapter 2. Doravirine (Pifeltro)
Figure 2. The central dogma of molecular biology
4, vide infra). In the heterodimeric protein of reverse
is the target of all currently approved reverse
3).
3,
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Chemistry and Pharmacology of Drug Discovery
one of the most frequent single-point mutations of reverse transcriptase is K103N, i.e.,
amino acid lysine (K) at position-103 of the wild-type virus is mutated to asparagine (N)
for the mutated virus. The use of one or two NRTIs usually led to rapid treatment failure
due to mutation. Novel antiretroviral drugs with a different mechanism of action were
9
needed to achieve sufficient virologic suppression.
Figure 3. Single-point mutation of HIV-1 reverse transcriptase
The first-in-class NNRTI was Boehringer Ingelheim’s nevirapine (Viramune, 9).
It was followed by Upjohn’s delavirdine (Rescriptor, 10) and DuPont–Merck’s efavirenz
(EFV, Sustiva, 11). These three antiretroviral drugs 9–11 are classified as the firstgeneration NNRTIs. Unfortunately, Pfizer decided to discontinue making delavirdine
(10) in 2018 based on a business decision and not for safety reasons.
All NNRTIs assume a “butterfly” type of conformation in noncompetitive
binding to the allosteric site of HIV-1 reverse transcriptase. In particular, they bind to a
NRTI
NNRTI
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hydrophobic domain known as the non-nucleoside inhibitor-binding pocket (NNIBP) that
is approximately 10 Å distal from the active subdomain of the DNA polymerase and
60 Å from the active site of RNase H in HIV-1 reverse transcriptase. This binding site is
non-existing in the unbound RT but it is created upon binding of an NNRTI. The binding
of an NNRTI to NNIBP influences the geometry of the reverse transcriptase active
catalytic site and interferes with viral DNA synthesis.
Chapter 2. Doravirine (Pifeltro)
10
Figure 4. The three-dimensional structure of HIV-1 reverse transcriptase, drawn using
PyMOL and coordinates from Protein Data Bank (PDB) file of 6UIS by Faridoon
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Chemistry and Pharmacology of Drug Discovery
As shown in Figure 4, the ribbon representation of the reverse transcriptase
active domain illustrates its hand-like structure with AZT (2, red dot on the hand at the
top right) in the active domain (D110, D185, and D186 as the catalytic triad) and
11
nevirapine (9, yellow) in the non-nucleoside binding pocket.
The allosteric binding site is not crucial to reverse transcriptase function and is
not directly involved in substrate binding or viral DNA synthesis. As a consequence,
point mutations can occur within the NNIBP that hinder NNRTI binding but do not
interfere
with reverse transcriptase’s role in viral DNA synthesis. Some of these
mutations make the virus resistant to NNRTI treatment. The general trends have shown
that mutations create a larger allosteric site.
The first-generation NNRTIs showed a significant loss of activity with singlepoint mutations, especially the two most prevalent single mutants, K103N and Y181C,
selected by nevirapine (9) and efavirenz (11). Second-generation NNRTIs, etravirine
(Intelence, 12) and rilpivirine (Edurant, 7) as diarylpyrimidines, largely overcome the two
mutants K103N and Y181C. Because of their conformational flexibility, these two
diarylpyrimidines can “wiggle” and “jiggle” to adapt to bind the mutated allosteric site of
NNIBP of the mutant reverse transcriptase. As a result, they exhibit prominent antiviral
12
activity toward of the clinically common mutations of K103N and Y181C.
However, second-generation NNRTIs suffer from poor aqueous solubility and
unfavorable pharmacokinetic properties although rilpivirine (7) has an improved
bioavailability than its prototype etravirine (12). Furthermore, other point mutations
within the NNIBP take place eventually, prominently K101P, E138R, and Y188L as
shown in Table
from severe rash as a severe adverse effect (SAE). Better NNRTIs are still needed.
13
1.
Some patients on either etravirine (12) or rilpivirine (7) also suffer
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Third-generation NNRTIs are represented by Merck’s doravirine (1), available
since 2018 in the United States. Elsulfavirine (Elpida, 13), a prodrug, is only approved in
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Russia
and ainuovirine (AiBangDe, 14) has been available in China since 2021.15
Generic Approval
Nevirapine (9) 1996 200 bid K103N, Y181C Liver toxicity
Delavirine (10)
Efavirenz (11) 1998 600 qd K103N, Y181C CNS AEs
Etravirine (12)
Rilpivirine (7)
Source: Adapted from Wang et al.
Chapter 2. Doravirine (Pifeltro)
Table 1. Key HIV-1 mutations
Dose
year
1997 400 qd K103N, Y181C Discontinued
2008 200 bid K101P, Y181C Severe rash
2011 25 qd E138R, Y188L Severe rash
(mg)
13
Key mutation Notes
Figure 5. Doravirine (1) specifically targets the allosteric binding pocket of HIV-1
reverse transcriptase. Source: Reproduced with permission from Elsevier
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