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CORRESPONDENCE
Year : 2008  |  Volume : 26  |  Issue : 2  |  Page : 202-203
 

An explanation in nanostructure level based on the view of energy change for G333d mutation relating to drug resistance in HIV-1 reverse transcriptase


Department of Laboratory Medicine, Wiwanitkit House, Bangkhae, Bangkok 10160, Thailand

Date of Submission17-Sep-2007
Date of Acceptance28-Nov-2007

Correspondence Address:
V Wiwanitkit
Department of Laboratory Medicine, Wiwanitkit House, Bangkhae, Bangkok 10160
Thailand
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0255-0857.40549

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How to cite this article:
Wiwanitkit V. An explanation in nanostructure level based on the view of energy change for G333d mutation relating to drug resistance in HIV-1 reverse transcriptase. Indian J Med Microbiol 2008;26:202-3

How to cite this URL:
Wiwanitkit V. An explanation in nanostructure level based on the view of energy change for G333d mutation relating to drug resistance in HIV-1 reverse transcriptase. Indian J Med Microbiol [serial online] 2008 [cited 2019 Nov 17];26:202-3. Available from: http://www.ijmm.org/text.asp?2008/26/2/202/40549


Dear editor,

Human immunodeficiency virus (HIV) infection is an important infection affecting a million of world population. The best present way in coping with the patients with HIV is controlling of disease with antiretroviral drugs. However, a new emerging problem of antiretroviral drug usage is the problem of drug resistance. Standardised surveillance of transmitted and treatment-associated HIV drug resistance is critical to the success of antiretroviral therapy expansion in developing countries. [1] DNA polymerase and RNAse H activities of HIV reverse transcriptase (RT) have been recognized as potential targets for antiretroviral therapy for many years. [1] The development of medicines targeting the DNA polymerase activity has been highly successful, with currently more than ten drugs approved for the treatment of HIV infection and more candidates in preclinical and clinical development. [2] However, the drug resistance due to the mutation of HIV-RT becomes a new interesting problem in HIV medicine. Mutations at G333D mutation within the reverse transcriptase (RT) gene cause resistance to both zidovudine (AZT) and lamivudine (3TC) in a background of mutations associated with loss of sensitivity to both drugs. [3] HIV strains containing both reverse transcriptase (RT) mutations are resistant to all of the approved NNRTI drugs. [3] In this work, the author simulated for the required energy corresponding to the G333D mutation of HIV-RT. This study can give an explanation in nanostructure level based on the view of energy change.

This is a calculation-based study. The quantum chemical analysis for overall reaction was performed according to the classical bonding theory. [3] Basically, each chemical reaction possesses its specific reaction energy. The primary assumption in this study is that the required reaction energy for the pharmacological reaction between antiretroviral drug and HIV-RT is equal to "A" kCal/mol for one mole of resultant complex. This parameter is a constant parameter. The net energy requirement in kCal for a reaction depends on the amount of two substrates, one mole of antiretroviral drug and one mole of HIV-RT. Here, another primary assumption is the amount of the two substrates is equal to "B" g and "C" g for antiretroviral drug and HIV-RT in general reaction with wild type of HIV-RT. However, the significant change in the mutants of HIV-RT is the amino acid, which disturbs the amount of the substrate HIV-RT. In this work, the theoretical simulation for the two mutants was performed. Calculation for the amount of HIV-RT in G333D mutation was done. Further calculation for the net energy requirement for a reaction was performed. For the G333D mutation, the main change is Gly (weight = 75.07 g/mol) to Asp (weight = 133.10 g/mol). The change in molecular weight due to this mutant and its corresponding net energy requirement are calculated and presented in the [Table - 1]. The net energy requirements of G333D mutation is less than wild type.

For G333D mutation, Zelina et al, reported that G333D increased the ability of HIV-1 RT to effectively discriminate between the normal substrate dCTP and 3TC-triphosphat and G333D also enhanced the ability of RT containing TAMs and M184V to bind template/primer terminated by AZT-monophosphate, thereby restoring ATP-mediated excision of AZT-MP under steady-state assay conditions. [4] In this theoretical research, the author tried to explain the energy change corresponding to the G333D mutation within HIV-RT. Here, the author found that both mutants critically affect the net energy requirement. Decreased energy requirement can be observed. It should be mentioned that not only the quantum energy change but also the conformational change due to mutation can be expected. These two phenomena bring the difficulties for occurrence of reaction and further imply the drug resistance. The results from this study can be useful for antiretroviral drug design and coping with the problem of G333D mutation HIV-RT-related drug resistance. This study can be a good model for further study in this area. The author suggests further studies on other mutants of HIV-RT and their effects on drug resistance.

 
 ~ References Top

1.Bennett DE. The requirement for surveillance of HIV drug resistance within antiretroviral rollout in the developing world. Curr Opin Infect Dis 2006;19:607-14.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Klumpp K, Mirzadegan T. Recent progress in the design of small molecule inhibitors of HIV RNAse H. Curr Pharm Des 2006;12:1909-22.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Gallego O, Corral A, de Mendoza C, Rodιs B, Soriano V. Prevalence of G333D/E in naive and pretreated HIV-infected patients. AIDS Res Hum Retroviruses 2002;18:857-60.  Back to cited text no. 3    
4.Zelina S, Sheen CW, Radzio J, Mellors JW, Sluis-Cremer N. Mechanisms by Which the G333D Mutation in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Facilitates Dual Resistance to Zidovudine and Lamivudine. Antimicrob Agents Chemother 2008;52:157-63.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]



 
 
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