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New HIV capsid inhibitors show high potency and prolonged activity in early studies
Liz Highleyman, 2017-03-03 07:20:00
A novel type of antiretroviral drug that
interferes with the assembly and disassembly of the HIV capsid, which encloses
the genetic blueprint of the virus, may offer a new potent and long-acting
treatment option if it continues to look promising in larger studies, according
to a presentation at the Conference on Retroviruses and Opportunistic
Infections (CROI 2017) last month in Seattle.
While current antiretroviral therapy is
effective and well tolerated for most people with HIV, new drugs that work in
different ways offer more options for putting together optimised regimens,
especially for treatment-experienced people with highly resistant virus.
Long-acting injectable drugs may be more convenient for some people and could
improve adherence. No HIV drugs with a novel mechanism of action have been
approved since the integrase inhibitors a decade ago.
Winston Tse presented findings from Gilead
Sciences' ten-year capsid inhibitor development programme, including the
promising candidate GS-CA1 – the first capsid inhibitor to enter pre-clinical
The HIV p24 capsid protein plays an essential
role in the viral lifecycle, forming a cone-shaped structure made up of
hexamers, or six-part subunits, that encloses the viral genome, Dr Tse noted as
Early laboratory studies led to the discovery of a novel class of
"exquisitely potent" and metabolically stable HIV capsid inhibitors
with promising pharmacokinetic profiles.
Tests of capsid binding and assembly, along with X-rays of the crystal
structure of capsid inhibitor candidates, enabled researchers to choose the
ones that bound most readily to HIV. They selected GS-CA1, which binds to a highly conserved site at the interface of two adjacent
molecules within a capsid hexamer.
Though designed to target capsid assembly, researchers
found that the inhibitor acts at multiple steps in the viral replication cycle,
interfering with capsid assembly necessary for late-stage virion (viral
particle) maturation, as well as functions that occur after entry into a host cell
such as capsid disassembly and moving viral genetic material into the cell
Laboratory human cell lines were used to test antiviral potency and drug
resistance. GS-CA1 is a highly potent inhibitor of HIV-1 replication, with a mean
50% effective concentration (EC50)
of 140 picomolar in peripheral blood mononuclear cells. Dr Tse said this
was "at least an order of
magnitude more potent" than existing antiretrovirals.
GS-CA1 demonstrated similar potency against multiple HIV-1 clinical
isolates from people with all major viral clades. It maintained full activity
against viral mutants resistant to all approved antiretroviral classes. It also demonstrated less potent activity
Though GS-CA1 had a high barrier to resistance, researchers could induce
resistance if they tried, Dr Tse said, resulting in unique capsid inhibitor
mutations (L56I, M66I, Q67H, N74D and A105E) that appeared to have reduced
Extensive metabolism and pharmacokinetic
profiling was done, showing that GS-CA1 is cleared slowly from the body and has
a long half-life. This makes it appear suitable for slow-release parenteral
administration, or long-acting injections.
Moving into animal studies,
a single subcutaneous injection of GS-CA1 given to rats maintained high plasma drug
levels well above the effective concentration for ten weeks. Gilead aims to move
into human trials using low-dose injections administered no more than once a
month, Dr Tse said.
So far GS-CA1 has shown no
measurable cytotoxicity in target cells. The company's goal is to proceed with
toxicology studies and enter phase 1 clinical trials in 2018, according to a Gilead press release.