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Identifying chemicals with potential therapy of HIV based on protein-protein and protein-chemical interaction network.

Li BQ, Niu B, Chen L, Wei ZJ, Huang T, Jiang M, Lu J, Zheng MY, Kong XY, Cai YD - PLoS ONE (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.

ABSTRACT
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.

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Related in: MedlinePlus

Three-dimensional structure of HIV-1 RT based on PDB structure 2VG7 drawn with software Pymol.HIV-1 RT is in green. Ligand is in orange, red and blue.
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pone-0065207-g004: Three-dimensional structure of HIV-1 RT based on PDB structure 2VG7 drawn with software Pymol.HIV-1 RT is in green. Ligand is in orange, red and blue.

Mentions: 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 (HIV-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 human’s right hand which contains the finger, palm, thumb, and connection subdomains (see Fig. 4). The finger subdomain includes β-sheets and three α-helices, and the palm subdomain contains five α-helices. These α-helices and β-sheets of finger and palm subdomains could form hydrogen bonding structure with four β-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 β-sheet and two α-helices [58], [59], [60]. P66 also looks like a right hand, and it makes up a large template-primer binding cleft of polymerase. The 3′-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 [61]. 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 [61]. As RT is a essential enzyme during the replication of HIV-1, lack of HIV-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).


Identifying chemicals with potential therapy of HIV based on protein-protein and protein-chemical interaction network.

Li BQ, Niu B, Chen L, Wei ZJ, Huang T, Jiang M, Lu J, Zheng MY, Kong XY, Cai YD - PLoS ONE (2013)

Three-dimensional structure of HIV-1 RT based on PDB structure 2VG7 drawn with software Pymol.HIV-1 RT is in green. Ligand is in orange, red and blue.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675210&req=5

pone-0065207-g004: Three-dimensional structure of HIV-1 RT based on PDB structure 2VG7 drawn with software Pymol.HIV-1 RT is in green. Ligand is in orange, red and blue.
Mentions: 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 (HIV-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 human’s right hand which contains the finger, palm, thumb, and connection subdomains (see Fig. 4). The finger subdomain includes β-sheets and three α-helices, and the palm subdomain contains five α-helices. These α-helices and β-sheets of finger and palm subdomains could form hydrogen bonding structure with four β-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 β-sheet and two α-helices [58], [59], [60]. P66 also looks like a right hand, and it makes up a large template-primer binding cleft of polymerase. The 3′-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 [61]. 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 [61]. As RT is a essential enzyme during the replication of HIV-1, lack of HIV-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).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus