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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: 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 addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins.The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying novel anti-HIV drugs.

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

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.
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pone-0065207-g005: 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.

Mentions: 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 5′-monophosphate analog, nucleoside 5′-diphosphate analog, and nucleoside 5′-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 3′-OH in these three chemicals, viral DNA could not grow after binding with the three chemicals. This could also prevent the HIV viruses’ reproduction.


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0065207-g005: 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.
Mentions: 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 5′-monophosphate analog, nucleoside 5′-diphosphate analog, and nucleoside 5′-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 3′-OH in these three chemicals, viral DNA could not grow after binding with the three chemicals. This could also prevent the HIV viruses’ reproduction.

Bottom Line: 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 addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins.The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying novel anti-HIV drugs.

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