Identifying Chemicals with Potential Therapy of HIV Based on Protein-Protein and Protein-Chemical Interaction Network
et al. (2013) Identifying Chemicals with Potential Therapy of HIV Based on Protein-Protein and Protein-Chemical
Interaction Network. PLoS ONE 8(6): e65207. doi:10.1371/journal.pone.0065207
Identifying Chemicals with Potential Therapy of HIV Based on Protein-Protein and Protein-Chemical Interaction Network
Bi-Qing Li 0
Bing Niu 0
Lei Chen 0
Ze-Jun Wei 0
Tao Huang 0
Min Jiang 0
Jing Lu 0
Ming-Yue Zheng 0
Xiang-Yin Kong 0
Yu-Dong Cai 0
Peter Csermely, Semmelweis University, Hungary
0 Current address: Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics , Saarbrucken , Germany
Acquired immune deficiency syndrome (AIDS) is a severe infectious disease that causes a large number of deaths every year. Traditional anti-AIDS drugs directly targeting the HIV-1 encoded enzymes including reverse transcriptase (RT), protease (PR) and integrase (IN) usually suffer from drug resistance after a period of treatment and serious side effects. In recent years, the emergence of numerous useful information of protein-protein interactions (PPI) in the HIV life cycle and related inhibitors makes PPI a new way for antiviral drug intervention. In this study, we identified 26 core human proteins involved in PPI between HIV-1 and host, that have great potential for HIV therapy. In addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins. All these indicate that our method as presented in this paper is quite promising. The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying novel anti-HIV drugs.
. These authors contributed equally to this work.
Human immunodeficiency virus (HIV) is a lentivirus belonging
to retrovirus family that causes acquired immunodeficiency
syndrome (AIDS) [1,2]. The global HIV and AIDS pandemic
has caused nearly 60 million infections. Experts estimate that more
than 25 million people have died of AIDS, and more than 33
million presently are living with HIV infection or AIDS .
During the last decade, the specific functions of HIV-1
encoded genes and related proteins have been extensively
studied, which facilitated the development of the effective
approved anti-AIDS drugs directly targeting the HIV-1 encoded
enzymes, including reverse transcriptase (RT), protease (PR) and
integrase (IN) [4,5]. Despite the great efforts in developing new
effective antiviral agents and the introduction of combination of
these drugs, namely highly active antiretroviral therapy
(HAART), the incidence of HIV infections continues to rise,
because of the rapid emergence of drug-resistant HIV-1 mutants
as well as the severe side effects. Therefore, there is an urgent
need for further improvement of the existing anti-HIV drugs 
and the introduction of novel drug design strategies  or novel
antiviral targets with therapeutic potential for HIV infection .
Recently, it has been reported that several human proteins that
were involved in HIV-1 life cycle and interactions with HIV-1
encoded proteins emerged as novel anti-HIV drug targets,
including TSG101 , NF-kB , positive elongation factor
PTEFb  and cellular factors related to nuclear import of
preintegration complex . Besides, small-molecule inhibition of the
direct protein-protein interactions (PPI) that mediate numerous
critical biological processes is an emerging area in current drug
Multiple PPI involved in many biological processes in the
HIV1 life cycle have been identified by genomics, proteomics and
biochemical approaches recently [17,18,19]. Although most of
these interactions are complicated and have not yet been fully
investigated, current knowledge on the molecular interactions has
significantly broadened the understanding of the HIV-1 life cycle
and paved an new way for the anti-HIV drug development. In
fact, there is an increasing number of examples of both chemical
and biological small molecular HIV inhibitors targeting PPI
emerging nowadays .
In this study, we compiled all the PPI from HIV-1, Human
Protein Interaction Database [17,18,19]. A PPI network was
constructed with all these human proteins based on STRING 
and 26 of them with a score greater than 1000 were selected
according to their betweenness. Then, 280 chemicals in STITCH
 that can interact with three HIV drugs targeting human
protein were identified. It has been shown that these 280 chemicals
can also interact with the 26 core human proteins. Therefore, the
280 chemicals and 26 human proteins may possess the potential
for HIV therapy. Our method may open a new way for HIV drug
design or at least plays a complementary role to the existing
Materials and Methods
HIV-1, Human Protein Interaction Data
All the protein-protein interactions (PPI) data were retrieved
from the HIV-1, Human Protein Interaction Database (http://
www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions/) [17,18,19]. It
includes 5,126 PPI and involves 19 HIV-1 proteins corresponding
to 9 HIV-1 genes as well as 1,450 human proteins corresponding
to 1,431 human genes. The PPI data was given in Additional File
Protein-Protein Interaction (PPI) Network
There are two PPI database: STRING (http://string-db.org/)
 and HPRD (http://hprd.org/) . The reasons why we
chose STRING over HPRD are as following:
1). The STRING database includes more PPIs than HPRD. So
far HPRD only contains 41,327 experiment supported PPI, while
STRING contains 1,640,707 PPI including both direct ones
(physical interactions) and indirect ones (functional interactions).
HRPD is more likely to be a subset of STRING, since STRING
includes the PPIs from experiments, existing databases,
textmining and predicted results.
2). The possible problems that the predicted PPIs with low
confidence in STRING would cause can be avoided in our
method. Since we used the weighted PPIs of STRING rather than
the binary ones, the confidence of each PPI is considered. If a PPI
has low confidence, it will be less important in Dijkstras algorithm
during the shortest path analysis, and most likely to be eliminated.
3). The PPIs in HRPD is not weighted. Therefore, it is difficult
to do quantitative network analysis. Overall, we selected STRING
to construct the PPI network. Each interaction in STRING is
evaluated by an interaction confidence score in range from 1 to
999 to quantify the likelihood that an interaction may occur. For
clarity, let Q(p1,p2) denote the interaction confidence score of two
proteins p1 and p2. The constructed network took proteins as its
nodes, and the edge between any two nodes existed if and only if
the corresponding proteins can interact with each other. To reflect
the difference of interactions, each edge with endpoints v1 and v2
in the network was labeled with a score as the edge weight as
W(v1,v2) = 1,0002Q(p1, p2)
Chemical-chemical Interactions and Protein-chemical
The data of chemical-chemical interactions and
proteinchemical interactions was retrieved from STITCH (version 3.0)
(http://stitch.embl.de/) , a well-known database containing
1,430,424 known or predicted chemical-chemical interactions
between 89,617 chemicals as well as 1,221,559 protein-chemical
interactions between 16,721 proteins and 234,826 chemicals
deriving from experiments, literature or other reliable sources.
Five scores with titles Similarity, Experimental, Database,
Textmining and Combined_score in range from 1 to 999
were used to indicate the interactivity of two chemicals or a
protein-chemical pair. Since the last score combines the
information of others, it was used as the final interaction score.
Shortest Path and Betweenness
For the given node in a network, its betweenness is related to the
number of the shortest paths connecting all pair of nodes such that
the node is the member of them . For the node in PPI
network, its betweenness accounts for direct and indirect
influences of proteins at distant network . Hence, betweenness
has been used for study various natural and man-made networks
[24,26,27,28]. However, it is not necessary to calculate each
nodes betweenness and consider all shortest paths. Here, we
proposed a new kind of betweenness, named as betweenness
related to A, where A was a node subset in a network. For this kind
of betweenness, we only calculated the betweenness of the node in
A not all nodes in the network. For a node d in A, its betweenness
related to A, denoted by BA(d), was calculated by the following
two steps: (1) Find shortest paths connecting all pair of nodes in A;
(2) Count the number of the shortest paths such that d was the
member of them.
Results and Discussion
26 Core Human Proteins Identified According to their
In our work, a protein-protein interaction network was
constructed for the 1,450 HIV interacting proteins based on
STRING. For each of the 1,450 proteins, its betweenness can be
calculated according to the method in Materials and methods.
In details, 1,050,525 shortest paths were found to calculate the
betweenness related to 1,450 proteins. If a node appears in more
than 0.1% of these shortest paths, it is deemed to be more
important than other nodes. Thus we selected 26 proteins with
betweenness greater than 1000, which were listed in Table 1. All
the betweennesses for these 1,450 proteins were given in
Additional File S2.
22 of these 26 proteins are well known to directly interact with
HIV proteins in previous studies (Table 1). Their interactions
include inhibition, activation, cleavage, degradation and so on (see
Additional File S1), which should be deemed as causative. The rest
four proteins may act as infection related, such as EGFR, which
was upregulated by HIV-1 Gag protein. According to the roles
played by these causative proteins during HIV life cycle, we briefly
classified them into three groups, which respectively take part in
receptor interaction, transaction and replication, and host immune
Within them, CD4 (cluster of differentiation 4) and CCR5 (C-C
chemokine receptor type 5) are acting as co-receptors for HIV
entry into targeting cells . CD4 is a glycoprotein expressing on
the surface of many kinds of immune cells such as macrophages,
monocytes and T-help cells, and dendritic cells. It is recognized as
the primary co-receptor of HIV targeting. It interacts with the
viral envelope glycoprotein (Env) to trigger a structural alterations
in Env and enable the virus to recruit other co-receptors, like
CCR5 or CXCR4 . The chemokine receptors CCR5,
member of the seven-transmembrane G protein-coupled receptor
superfamily, is one of the principal co-receptors for majority HIV
isolates. It interacts with HIV protein gp120 so that HIV gp41
*Directly interact with HIV proteins.
proteins shape were changed to penetrate the cell membrane .
A natural mutant CCR5D32 (32 base pair deletion) can provide
highly protection in HIV infected individuals in homozygous state
[32,33]. Besides, the small guanosine triphosphate hydrolase
(GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1) is
reported to positively regulates co-receptor CXCR4 function .
The proteins mainly related to HIV transaction activity and
replication in our result include TP53, EP300, STAT1, STAT3,
GRB2, NF-kB complex subunit, polyubiquitin-C, Akt-1,
interferon gamma, MAPK8, beta-catenin, SRC1, SP1, Bcl-2. Cellular
tumor antigen p53 (TP53), a tumor suppressor participating in
multiple pathway like cell cycle arrest or apoptosis, interacts with
HIV-1 viral infectivity factor (Vif) to mediate G2 cell cycle arrest
with a positive effect on HIV-1 replication . Histone
acetyltransferase p300 and SP1 interact with HIV-1 Viral
protein-R (Vpr) to mediate Vpr activity in virion assemble,
nucleus locating, promoter activation, cell cycle arrest or apoptosis
induction . In addition, Histone acetyltransferase p300,
GRB2, Polyubiquitin-C, Akt-1, MAPK8 are all involved in the
HIV trans- activating protein Tat mediated transactivation of
HIV-1 LTR and viral replication, respectively [37,38,39,40,41].
Several proteins are to function by the similar pathway, such as the
NF-kB signaling pathway or JAK-STAT pathway. Nuclear factor
(NF)-kB complex is a master regulator of pro-inflammatory genes
and is upregulated in HIV-1 infection. It plays a key role in the
adaptive immune responses mounted against viruses, however, in
addition to the protective effect, NF-kB may also contribute to
viruses replication, survival and spread [42,43,44]. The
JAKSTAT pathway usually transmits information from chemical
signals outside the cell and involved in regulation of the immune
system. Here, it includes Interferon gamma, STAT3, beta-catenin
to regulate the HIV replication in astrocytes . This also
explains that the key proteins in these pathways ranking higher in
The rest proteins are associated with the immune response
against HIV infection. Interleukin-2 (IL-2), a secreted cytokine, is
observed increasing in early CD4+ T-cell response for HIV-1
infection to control viral replication , though this response will
lose function with the disease processing . Transcription factor
AP-1 is recruited by HIV Nef protein to MHC-I cytoplasmic tail
to disrupt the presentation of HIV-1 epitopes to anti-HIV
cytotoxic T lymphocytes . The aberrant changes in
pp125FAK expression block the beta1 integrin-mediated
protection effect for aberrant cell death in patients with AIDS .
Integrin alpha-4 expressed on NK cells is bound by HIV gp120 to
suppressing NK cells . JAK-STAT pathway is also responsible
for the antiretroviral effect of IFN-gamma, and the Jak/STAT
deficiency may contribute to the dysfunction of CD4 T cell
responses to a cytokine like IL-2 by HIV [51,52].
Chemicals Related to 26 Core Human Proteins
Three approved HIV drugs targeting human proteins in
Drugbank were collected (Table 2).
For each of the three HIV related drugs, its interactive
chemicals in STITCH can be found. After collecting these
chemicals and combining with the three drugs, we obtained 280
chemicals (Additional File S3). For each of 26 proteins, we can
count the number of the interactive chemicals among these 280
chemicals. Figure 1 shows the number of interactive chemicals
among 280 chemicals. From Fig. 1, we can see that the number of
chemicals related to ENSP00000011653 (CD4) is the largest,
followed by that of ENSP00000292303 (CCR5). The chemicals
related to each of the 26 proteins were ranked according to their
interaction score (see Additional File S4).
Chemicals Targeting Interaction between HIV and
CCR5, a membrane protein, is an important target of anti-HIV
therapy as it is one of the major co-receptors for HIV-1infection.
There are seven trans-membrane helix structures in CCR5, which
formed a pocket structure (Fig. 2) . In this pocket,
aromatic amino acid residuals, hydrophobic amino acid residuals,
polar amino acid residuals and hydrophilicity amino acid residuals
could bind with chemicals by p-p stacking interaction,
hydrophobic interaction, hydrogen bonding interaction and salt-bridge
For ENSP00000292303 (CCR5), it can be found that some
chemicals with interaction score higher than 900 are very similar
in sub-structure (Fig. 3). Among these chemicals, CID100483407
(maraviroc) (Table 2) is a known anti-HIV drug which could bind
with CCR5. As for chemicals CID105479787 (SCH 351125),
CID100183789 (TAK-779), CID103009355 (vicriviroc),
CID105275741 (TAK-652), CID100464036 (AD101), they are
very similar to CID100483407 (maraviroc) in sub-structure. We
speculated these chemicals may also have the same target CCR5.
From Figure 3, it can be seen that all these chemicals have three
hydrophobic structures containing basic nitrogen atoms (nitrogen
atoms in bridge chain, piperidine ring, ammonium salt) and amide
group. The three hydrophobic structures can interact with
hydrophobic amino acid or hydrophobic structures of
transmembrane by hydrophobic interaction or p-p stacking interaction
like CID100483407 (maraviroc). Benzene ring and Triazole ring
of CID100483407 (maraviroc) can insert into hydrophobic pocket
and form T shape p-p stacking by interacting with Tyrosine
(Tyr108) and tryptophan (Trp86). In addition, cyclohexyl group of
CID100483407 (maraviroc) can interact with isoleucine (Ile198) to
form hydrophobic interaction. Furthermore, the interaction
between basic nitrogen atoms in bridge chain of CID100483407
(maraviroc) and hydrophilicity amino acid residuals of CCR5
forms salt-bridge which is the major binding modes. Similar to
CID100483407 (maraviroc), basic nitrogen atoms in bridge chain
of CID105479787 (SCH 351125) can also form salt-bridge with
glutamic acid (Glu283). Methylbenzene and formyl pyridine ring
at nitrogen atom could form p-p stacking structure with
tryptophan 86 and 248 (Trp86, Trp248), respectively. Meanwhile,
acetyl group of piperidine ring and isoleucine (Ile198) could form
hydrophobic structure. As for the other chemicals like
CID100183789 (TAK-779), CID103009355 (vicriviroc),
CID105275741 (TAK-652), CID100464036 (AD101), they are
similar to CID100483407 (maraviroc). Therefore, they may be
also considered as potential anti-HIV drugs targeting CCR5.
Figure 3. Structures of 6 chemicals whose interaction scores with ENSP00000292303 (CCR5) are greater than 900. The figure was
generated using ChemAxon. The 6 chemicals are CID100483407 (maraviroc), CID105479787 (SCH 351125), CID100183789 (TAK-779), CID103009355
(vicriviroc), CID105275741 (TAK-652) and CID100464036 (AD101), which can also be found in PubChem with the IDs 483407, 5479787, 183789,
3009355, 5275741, and 464036, respectively.
Chemicals Targeting Interactions Involving HIV-1 Reverse
It can be found that some chemicals whose interaction score are
higher than 740 for ENSP00000011653 (CD4) are also similar in
sub-structure. Most of these chemicals are related to HIV-1
reverse transcriptase (HIV-1 RT) and HIV-1 Protease
1 PR). HIV-1 RT is a hetero-dimeric enzyme which is composed
of two distinct subunits P66 and P51 [58,59]. The peptide
sequence of P51 is identical to the first 440 amino acids of P66,
and they form the two subunits of polymerases domain. The
subunit looks like humans right hand which contains the finger,
palm, thumb, and connection subdomains (see Fig. 4). The finger
subdomain includes b-sheets and three a-helices, and the palm
subdomain contains five a-helices. These a-helices and b-sheets of
finger and palm subdomains could form hydrogen bonding
structure with four b-sheets of thumb subdomain. The hand of
the domain and the RNase H domain is connected by connection
subdomain which is composed of a big b-sheet and two a-helices
[58,59,60]. P66 also looks like a right hand, and it makes up a
large template-primer binding cleft of polymerase. The 39-OH
terminus of the primer is positioned close to active site of
polymerase (three catalytic amino acid residuals: Asp110, Asp185
and Asp186). P51 is processed by proteolytic cleavage of P66,
which is different from P66 in structure although their amino acid
sequences are similar . The finger of P51 is close to the palm,
and there is no template-primer binding cleft. As the active sites
are buried, there is no catalytic activity for P51. Hence each P66/
P51 dimer has only one active site which is located in P66. When
HIV infects the host cell, HIV-1 RT creates single-stranded DNA
from the RNA template. First, RT binds to RNA. Then the
corresponding DNA nucleoside of host cell binds to phosphate
group as substrate, and copy RNA nucleotide . As RT is a
essential enzyme during the replication of HIV-1, lack of
1 RT could block the HIV-1 replication cycle, thus preventing
HIV reproduction. Therefore, RT is regarded as an important
anti-HIV target. At present, RT inhibitors could be classified to
nucleoside analog reverse-transcriptase inhibitors (NARTIs) and
non-nucleoside reverse-transcriptase inhibitors (NNRTIs).
Among the chemicals with score greater than 740,
CID100003043 (didanosine) (Table 2) is a known anti-HIV drug
targeting HIV-1 RT. Intriguingly, we found that CID100005726
(zidovudine) and CID100005155 (stavudine) may also bind to
HIV-1 RT. These three chemicals are nucleoside analog which
are very similar to RNA and DNA in structure (Fig. 5). Nucleoside
analogs could be phosphorylated when they enter the cells. Then
they compete with natural deoxynucleotides for binding with RT,
thus inhibit the usage of nucleoside substrates by RT, arrest the
growing of viral DNA and prevent viruses reproduction
[62,63,64]. In this study, CID100005726 (zidovudine),
CID100005155 (stavudine), CID100003043 (didanosine) are
phosphorylated to nucleoside 59-monophosphate analog,
nucleoside 59-diphosphate analog, and nucleoside 59-triphosphate
analog, respectively, after the three chemicals enter the cells.
Then the three analogs could bind with RT instead of natural
nucleoside phosphate substrates (dTTP, dCTP, dATP, dGTP). As
a result, the binding between natural nucleoside substrates and
HIV-1 RT is blocked, and the HIV-1 RT is competitively
inhibited. On the other hand, as there is no 39-OH in these three
chemicals, viral DNA could not grow after binding with the three
chemicals. This could also prevent the HIV viruses reproduction.
Other chemicals targeting HIV-1 RT including CID100060847
(BHAP), CID100004463 (nevirapine), CID105495818
(BMS378806) could be classified to NNRTIs. Different to NARTIs,
NNRTIs have two symmetrical aromatic rings, which show special
butterfly-like shape (Fig. 6) [65,66]. Five b-sheets of P66 form a
pocket which is composed of hydrophobic amino acids. Based on
hydrophobic, hydrogen bonding and p-p stacking interaction
derived from aromatic ring of aromatic amino acids, the aromatic
rings from one side of these three chemicals can interact with
aromatic amino acids including Tyr181, Tyr188, Phe227, Trp229
and those from another side can interact with hydrophobic amino
acids including Val179, Val106 and Leul00. Therefore, a small
hydrophobic pocket is formed by Tyr181, Tyr183 and Tyr188. As
the three amino acids rotate outside, the entrance of the pocket
will be exposed where HIV-1 RT can bind to these three
chemicals. In this case, the relative locations of b4, b7 and b8
sheets will change. Complementary rearrangement of the
conformation of RT and CID100060847 (BHAP), CID100004463
(nevirapine), CID105495818 (BMS-378806) result in hydrophobic
interactions [64,67,68]. As a result, the conformation of the newly
located catalytic active site is similar to that of P51 . Therefore,
the new conformation is inactive. This is the reason why
nonnucleoside analog has the ability to inhibit the RT by changing the
conformation of catalytic site.
Chemicals Targeting Interactions Involving HIV-1
HIV-1 protease is a C2-symmetric homodimer including two
monomers which have the identical polypeptide sequence with 99
residues (see Fig. 7) . There is an active site (Asp-Thr-Gly) in
the region between P25 and P27. The two subunits are connected
by four b anti-parallel strands containing glycine, and each strand
contains N-terminal domain and C-terminal domain. Both the
monomers have a long cavity structure, on the bottom of which
lie the catalytic aspartyl residues with planar configuration [69,70].
Due to the special structure of HIV-1 PR, the substrate peptide
binds to the enzyme in an extended anti-parallel b sheet through
the amino acid side chains from completely opposite directions
. It should be noted that the two subunits of enzyme are not
completely identical, although they are symmetrical. Both the
monomers have a flap structure which is made up of antiparallel
b strands extending to subsite P1 and P2 . Due to the different
conformation of flap of the two subunits, such a symmetrical
conformation has the ability to recognize particular amino acid
residues to control the substrates/inhibitors access.
Both CID100003706 (indinavir) and CID100005076 (ritonavir)
are peptidic chemicals which could compete with natural
substrates as the substrates of HIV-1 PR. During the process of
hydrolysis of peptide bonds of these two chemicals, one active
water molecule is polarized by carboxyl group of Aspartyl residue.
Nucleophilic O-atom of water attacks the carbonyl of the
substrates scissile bond to form a tetrahedral intermediate which
could further become amino and carbonyl chemical. Then the
hydroxy and carboxyl group form hydrogen interacts with
Aspartate as hydrogen bond acceptor and donor, respectively.
Meanwhile, aromatic rings of side chain of these two chemicals
firmly bond to active region of protease through electrostatic and
steric interactions. As a result, the conformation of flap changes
and a tunnel structure which go through the dimmer obliquely
forms in the active region. Then the symmetrical conformation of
protease is broken and the flexible region closes. Eventually,
1 PR is inhibited by damaging its activity.
Figure 5. Structures for 3 chemicals whose interaction scores with ENSP00000011653 (CD4) are greater than 740. The figure was
generated using ChemAxon. The 3 chemicals are CID100003043 (didanosine), CID100005726 (zidovudine) and CID100005155 (stavudine), which can
also be found in PubChem with the IDs 3043, 5726 and 5155, respectively.
Miglustat may also Target HIV-1 Protease
Miglustat is another approved drug for HIV in Drugbank with
the identity of CID100051634 (Table 2). It was revealed by our
result that CID100051634 is also related to ENSP00000011653
(CD4), though interaction score of CID100051634 is only 359.
However, it can be found that the structure of CID100051634 is
still similar to the sub-structure of peptidic chemical. And the
related studies show that CID100051634 also have anti-HIV
activity in experiment. CID100051634 is an N-alkylated imino
sugar. Clinical trials show that CID100051634 alter the
glycosylation of envelope glycoproteins and decrease the infectivity in
certain viral diseases such as HIV . Carefully study
CID100051634, we can found that CID100051634 has three
hydroxyl groups which can interacts with Aspartate as hydrogen
bond acceptor and donor, respectively. Therefore, we presume
CID100051634 may also target HIV-1 PR.
New Combinations of HAART Proposed by
A combination of HAART generally includes two NARTIs and
one drug in the following classes: NNRTI, protease inhibitor (PI),
integrase strand transfer inhibitor (INSTI), or a CCR5 antagonist.
According to the presumption that two interactive chemicals are
more likely to share similar biological functions [74,75,76], we
attempted to propose some new combinations of HAART through
substituting the original components for their interactive
chemicals. One way is replaced by inhibitors in the same class. NIH
proposed some preferred regimens of HAART with optimal,
durable efficacy, favorable tolerability and toxicity profile ,
such as atazanavir/ritonavir+tenofovir disoproxil
fumarate/emtricitabine (ATV/r+TDF/FTC). TDF/FTC is often used as a
backbone for boosted PI-based regimens in the initial treatment of
HIV-1 infection . Therefore, we attempted to substitute ATV
for other PIs. We found 166 interactive chemicals of atazanavir
from STITCH [22,79]. Except sulfate, eight interactive chemicals
with the highest confidence score are PIs, including lopinavir
(LPV), darunavir (DRV), ritonavir (RTV), saquinavir (SQV),
fosamprenavir (FPV), nelfinavir (NFV), amprenavir (APV), and
indinavir (IDV). All of these eight interactive chemicals related to
ENSP00000292303 (CCR5), which is also shared by ATV. The
combinations of one of the first five PIs with TDF/FTC are
recognized regimens for anti-HIV-1 therapeutics by NIH .
NFV+TDF/FTC is also used for clinical AIDS treatment,
although this medication may cause life-threatening lactic acidosis
. APV combined with TDF/FTC have been observed to have
additive synergistic effects for antiretroviral therapy . Thus, it
is reasonable to assume the validity of IDV+TDF/FTC for the
treatment of AIDS, but it need the safety assessment.
Another way is substituted for inhibitor in different classes. For
example, Trizivir (abacavir+lamivudine+zidovudine,
ABC+3TC+AZT) is recommended as an initial antiretroviral therapy .
Here we took 3TC+AZT as a backbone, and substituted ABC for
inhibitors in different classes. Three inhibitors with the highest
interaction score, efavirenz (EFV), nevirapine (NVP) and
delavirdine (DLV), are NNRTIs. ABC and its three interactive
chemicals are associated with ENSP00000011653 (CD4) and
ENSP00000292303 (CCR5). EFV or NVP with 3TC+AZT are
recognized by NIH , so we thought it was feasible to use
DLV+3TC+AZT for antiretroviral therapy.
At present, there is a great need for alternative way of inhibition
for the design of anti-HIV therapeutics, because of the increased
resistance of HIV to already approved drugs. Recently, inhibition
of protein-protein interactions in the HIV life cycle is increasingly
recognized as a valuable new avenue in drug design. In this work,
we identified 26 core human proteins which play important roles
in the HIV life cycles by interacting with HIV encoded proteins.
In addition, 280 chemicals that interact with three HIV drugs
targeting human proteins can also interact with these 26 core
proteins. Therefore, the 280 chemicals may possess the potential
for HIV therapy through intervention of PPI between 26 core
human proteins and HIV encoded proteins. Our method may
open a new way for HIV drug design or at least plays a
complementary role to the existing method.
The information of 280 chemicals.
The authors wish to thank the editor for taking time to edit this paper. The
authors would also like to thank the two anonymous reviewers for their
constructive comments, which were very helpful for strengthening the
presentation of this study.
Conceived and designed the experiments: XYK YDC. Performed the
experiments: BQL LC. Analyzed the data: BN LC MJ JL. Contributed
reagents/materials/analysis tools: ZJW TH MYZ. Wrote the paper: BQL
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