Future
Medicinal
Chemistry
Review
part of
Future Med. Chem. (Epub ahead of print) ISSN 1756-8919 10.4155/fmc.16.3 © 2016 Future Science Ltd
The current anti-HIV combination therapy does not eradicate the virus that persists
mainly in quiescent infected CD4
+
T cells as a latent integrated provirus that resumes
after therapy interruption. The Tat-mediated transactivation (TMT) is a critical step in
the HIV replication cycle that could give the opportunity to reduce the size of latent
reservoirs. More than two decades of research led to the identification of various
TMT inhibitors. While none of them met the criteria to reach the market, the search
for a suitable TMT inhibitor is still actively pursued. Really promising compounds,
including one in a Phase III clinical trial, have been recently identified, thus warranting
an update.
First draft submitted: 30 September 2015; Accepted for publication: 15 January 2016;
Published online: 2 March 2016
Keywords: CDKinhibitors•dCA•didehydrocortistatineA•functionalcure•HIVlatency•
HIVreservoir•HIVtranscriptioninhibitors•PPI•TARligands•Tatinhibitors•transactivation
The combined antiretroviral therapy (cART)
has profoundly changed HIV infection from
a debilitating fatal to a chronic manageable
disease, however, 30 years after the discovery
of HIV, a ‘cure’ does not exist yet. The cART
successfully suppresses HIV viral load to an
undetectable level and radically improves
the life quality of HIV/AIDS patients, also
thanks to the introduction of multicompo-
nent drugs such as Triumeq
®
(ViiV Health-
care), Prezcobix
®
(Janssen Therapeutics)
and Evotaz
®
(Bristol–Myers Squibb), just to
mention the newest. However, the benefts
of such of drugs cocktails are often compro-
mised by several factors such as side effects,
the emergence of HIV drug-resistant strains
and the impossibility to eradicate the virus.
The causes of the HIV infection persistence
appear to be multifaceted, but the major bar-
rier to the HIV eradication is due to the reac-
tivation of the virus from long-lasting reser-
voirs of HIV in the form of integrated viral
DNA in resting CD4
+
T-memory cells. The
combination of longevity and lack of actively
replicating virus makes current therapy inad-
equate to eliminate such reservoirs, which
thus are ideally suited to hide copies of the
virus able to trigger a new systemic infection
upon discontinuation of therapy [1] .
More effective anti-HIV agents are clearly
still needed. A promising step in the HIV
life cycle that could give the opportunity to
reduce the size of the latent reservoirs, thus
accelerating the HIV eradication, is the
Tat-mediated transactivation (TMT).
Briefy, transcription from HIV promoter
is a complex and multistage process that
is carried out by the RNA polymerase II
(RNApII), along with the cooperative action
of both viral and cellular factors (Figure 1) .
Within this process, the viral transactivator
Tat plays a major role in substantially increas-
ing the production of elongated transcripts.
In the basal transcription, RNApII ef f-
ciently initiates transcription from the HIV
promoter but pauses after the synthesis of
short RNAs that include the trans-activating
region (TAR), due to the cooperative action
Recent advances in the identification of
Tat-mediated transactivation inhibitors:
progressing toward a functional cure of
HIV
Oriana Tabarrini*
,1
, Jenny
Desantis
1
& Serena Massari
1
1
DepartmentofPharmaceuticalSciences,
UniversityofPerugia,ViadelLiceo1,
06123Perugia,Italy
*Authorforcorrespondence:
Tel.:+390755855139
Fax:+390755855115
oriana.tabarrini@unipg.it
For reprint orders, please contact reprints@future-science.com