Fostemsavir is a new anti-HIV-1 drug, that has been approved 2nd of July 2020. You can find all the structural relations and intermolecular interaction of the drug and the active site.

1. SerenaZ.Hijazeen

2. Serena Z. Hijazeen
OUTLINE

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HIV OVERVIEW

4. Serena Z. Hijazeen
◊ Most people with HIV if kept under the right antiviral drugs daily will not develpe AIDS
◊ A person with HIV is considered to have progressed to AIDS when
• The number of CD4 cells falls below 200 cells/mm3.
• When they start developing one or more opportunistic infections regardless of their CD4 count
◊ Without the proper treatment, people may survive 3 years with AIDS.
◊ In the presence of another opportunistic infection, survival rate falls to 1 year
HIV OVERVIEW
A statement made by the FDA
There is no vaccine currently
available

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The virus epidemic started in the US around June 1981, and till now there
have been no official drug for the cure because viruses have high mutation
rates than other microbes.
TREATMENTS OVER THE YEARS
•Approved in
1987
•NRTIs
Zidovudine
•Approved in
2011
•NNRTIs
Rilpivirine
•Approved in
1996
•PIs
Ritonavir
•Approved in
2003
•FIs
Enfuvirtide
•Approved in
2007
•CCR5 antagonist
Maraviroc
•Approved in
2017
•IIs
Raltegravir
•Approved in
2018
•Post-attachment
inhibitr
Ibalizumab-
uiyk
•Approved in
July/2020
•Attachment
inhibitor
Fostemsavir

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FOSTEMSAVIR
It is an
antiretroviral
drug
The first in its
class
(attachment
inhibitors)
It was
developed by
ViiV healthcare
They filled a
NDA1 with the
FDA in
December 2019
A marketing
authorization
application was
submitted to
the EMA2 in Jan
2020
The FDA
approved the
drug in July
2020
1: New drug application
2: European medicine agency

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MECHANISM OF HIV INFECTION
HIV is a retrovirus,
which means it
carries single-
stranded RNA is its
genetic material
rather than the
double-stranded
DNA human cells
carry.
Retroviruses also
have the enzyme
reverse
transcriptase,
which allow it to
copy RNA into
DNA and use that
DNA "copy" to
infect human, or
host, cells.
When HIV infects
a cell, it first
attaches to and
fuses with the
host cell.
Then the viral RNA
is converted into
DNA and the virus
uses the host cell’s
machinery to
replicate itself
during a process
called reverse
transcription.
The new copies of
HIV then leave the
host cell and move
on to infect other
cells.

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→Fostemsavir also referred to as GSK3684934, is a prodrug that is metabolized to Temsavir
TMR (GSK2616713).
→It is the first in its class to inhibit viral attachment and entry to the host cell, by binding
directly to the gp120 subunit present in the HIV-1 envelope glycoprotein gp160 on the
surface of the virus.
The active
form that is
absorbed to
the blood
Fostemsavir Temsavir
Activation of FTM
MECHANISM OF FOSTEMSAVIR ACTION

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MECHANISM OF FOSTEMSAVIR ACTION
→Rukobia is an HIV-1 gp120-directed attachment
inhibitor.
→This blocks the interaction of the virus with the
cellular CD receptors on the host immune system and
prevents its attachment.
→Temsavir can also block the other gp120-dependent
processes after the attachment crucial for viral entry.

10. Substitution of the benzamide phenyl ring was generally poorly tolerated, although 2-pyridyl and some five-
membered heterocycles, particularly thiophenes and furans, were acceptable replacements.
The introduction of small substituents to the piperazine ring proximal to the glyoxamide moiety could be
beneficial; however, this was context-dependent and small alkyl moieties were often prone to metabolic
modification.
The glyoxamide element was found to be optimal for the indole-based series, and while there was tolerance for
limited substitution at C-4 of the heterocycle, substitution at the C-5 and C-6 positions were poorly tolerated as
was replacing C-5 with a N atom.
However, replacing C-6 with a N atom was more readily accommodated, associated with a modest 5-fold
reduction in antiviral activity when compared to the parent indole.

11. Further SAR studies showed that there was considerable scope for the introduction of substituents at C-7, with
many amides and heterocycles conferring enhanced antiviral potency that also broadened the functional
spectrum of inhibition.
Replacements for the benzamide moiety were also explored extensively because this turned out to be a labile
metabolic site in humans.
Many structural elements that preserved the overall topology of the benzamide element demonstrated potent
antiviral activity, with the microbicide candidate (BMS-599793, DS-003) and the tetrahydroisoquinoline being
representative examples, although compounds with a profile suitable for development proved to be elusive.
BMS-599793, DS-003
tetrahydroisoquinoline FTR

12. X-ray structure of the cocrystal of the complex of gp120 with Temsavir showing that the AI binds
between the inner and outer domain of gp120 and under the β20−β21 loop.
The AI predominantly interacts with gp120 via hydrophobic interactions and forms H-bonds with D113
from the α1-helix of the gp120 inner domain and W427 of the outer domain.
The benzamide moiety occupies the site of gp120 that is occupied by W427 in the open state such that
W427 and the β20−β21 loop are pushed toward the CD4 binding loop, thereby blocking CD4 binding.

13. The safety and efficacy of Rukobia, taken twice daily by mouth, were evaluated in a
clinical trial of 371 heavily treatment-experienced adult participants who continued to
have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs.
In a multiple-ascending-dose study of FTR in participants with HIV, the average plasma
half-life of TMR was 3.2 to 4.5 hours (IR) and 7 to 14 hours (ER).
TMR is largely cleared by biotransformation, primarily via esterase-mediated hydrolysis
and CYP450-mediated oxidation.
UGT-mediated glucuronidation has a minor role in TMR metabolism.
Following a single dose of FTR administered to healthy male participants, 44–51% of the
dose was excreted in urine, 33% in feces, and 5% in bile
Pharmacokinetics

15. TMR is neither an
inducer nor inhibitor of
major CYP or UGT
enzymes; however,
TMR is metabolized in
part by cytochrome
CYP3A4. TMR is also a
P-gp and BCRP
substrate.
• TMR and/or its metabolites inhibit BCRP1, OATP1B1, and OATP1B32.
• Dose adjustments are not necessary when FTR is co-administered with currently approved ARV drugs3
across all classes. Dose modifications are also not required when co-administering FTR with any of the
following: drugs that increase gastric pH, strong CYP3A inhibitors, moderate CYP3A inducers, and opioid
dependence therapy
• Strong CYP3A inducers can significantly reduce plasma concentrations of TMR; therefore, the co-
administration of FTR with strong CYP3A inducers is contraindicated.
• Due to TMR inhibition of OATP1B1 and OATP1B3 and the potential for increased grazoprevir plasma
concentrations, the co-administration of FTR with elbasvir/grazoprevir is contraindicated.
• Dose modifications of certain statins may be necessary when FTR is administered with certain statins
• When co-administering FTR with estrogen-based therapies..
• FTR should be used with caution when given with drugs that are known to prolong the QT interval.
DDIs
1: Breast Cancer Resistance Protein
2: Hepatic Organic Anion Transporting Polypeptides
3: Antiretroviral Drugs

16. REFERNCES
1. https://www.hiv.gov/hiv-basics/overview/about-hiv-and-
aids/what-are-hiv-and-
aids#:~:text=HIV%20(human%20immunodeficiency%20virus
)%20is,to%20other%20infections%20and%20diseases.
2. https://ccr.cancer.gov/news/landmarks/article/first-aids-
drugs
3. https://aidsinfo.nih.gov/understanding-hiv-aids/fact-
sheets/21/58/fda-approved-hiv-medicines
4. https://www.clinicaltrialsarena.com/projects/rukobia-
fostemsavir-for-the-treatment-of-hiv/
5. https://pubs.acs.org/action/showCitFormats?doi=10.1021/a
cs.jmedchem.7b01337

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