Chemistry Reference
In-Depth Information
The fundamental role of lectins in cellular recognition has gained remarkable attention by several research groups,
which has brought about great advances in this field, with the discovery of myriad functions and applications of
lectins [9, 10]. For instance, the investigation of carbohydrate-lectin interactions has allowed the design of drugs
based on natural glycan structures with high capacity to interact with specific binding sites, such as those explored
for treatment of virus infections and parasitic diseases.
HIV Virus and Drug Design
A crucial feature of the human immunodeficiency virus (HIV) is the presence of complex carbohydrates (glycans)
that surround the exposed envelope. However, HIV genome encodes no gene products capable of synthesizing these
carbohydrates, being the surface proteins glycosylated by host cellular enzymes. It is well known that this
glycosylation process affects significantly the folding of viral glycoproteins, the transmission of the virus and nature
of the immune response to infections [11].
The comprehension of the viral life cycle has lead to the identification of targets for drug design. Twenty-five anti-
HIV drugs have been formally approved for the treatment of AIDS, which can be divided in seven main categories,
as shown in Table
3
. Furthermore, novel anti-HIV drugs are under clinical and preclinical trials related with these
viral targets and others, which are involved in viral adsorption processes (mediated by gp 120 glycoprotein), proviral
DNA integration or transcription transactivation (Fig.
3
) [12a, 12b].
Table 3:
Viral Targets and Approved Anti-HIV Drugs.
Viral Targets
Anti-Hiv Drugs
zidovudine, didanosine, zalcitabine, stavudine, lamivudine,
abacavir, emtricitabine
nucleoside reverse transcriptase inhibitors (
NRTIs
)
nucleotide reverse transcriptase inhibitor (
NtRTI
)
tenofovir disoproxil fumarate
non-nucleoside reverse transcriptase inhibitors (
NNRTIs
)
nevirapine, delavirdine, efavirenz, etravirine
saquinavir, ritonavir, indinavir, nelfinavir, amprenavir,
lopinavir, atazanavir, fozamprenavir, tipranavir, darunavir
protease inhibitors (
PIs
)
fusion inhibitor (
FI
)
enfuvirtide
co-receptor inhibitor (
CRI
)
maraviroc
integrase inhibitor (
INI
)
raltegravir
The first step in the initiation of infection is the recognition and promoting of cell-virus interactions of a virus
particle to a specific receptor on the surface of the target cell. In the HIV and other enveloped viruses, the interaction
with the cell receptor is mediated by the envelope glycoprotein. The viral envelope is constituted by a lipid bilayer
containing a complex protein denominated
env
that consists of glycoproteins gp41 (transmembrane) and gp120,
exposed to the viral surface and anchored (bound non-covalently) to gp41. The receptor for HIV is the CD4
lymphocyte; when the virus approaches the host cell, the gpl20 of HIV binds to CD4. This is the first identified
retroviral receptor and also the one most extensively studied [13, 14]. The modulation of the antigenicity of gp120 is
dependent on the extension and variability of surface glycosylation and represents an interesting target to be
explored in drug design [15].
Carbohydrate-Binding Agents (CBAs)
Taking into account the important role developed by glycans in viral infections, agents that interact with these
viral envelope glycans may prevent the efficient entry of the virus into its susceptible target cells. Furthermore,
these carbohydrate-binding agents (CBAs) may force the virus to delete part of its surface glycans to escape
drug pressure, which can lead to the initiation of an immune response against exposed immunogenic envelope
epitopes. Thus, the antiviral mechanisms of the CBAs may comprise direct antiviral activity by binding to
glycans of the viral envelope, avoiding virus entrance, and indirect antiviral action from the constant deletions
of the envelope glycan shield, triggering the immune system to act against previously hidden immunogenic
epitopes of the viral envelope [16].
