NIAID HIV/OI Searchable Chemical Database

Nucleoside Analogs

Nucleoside analogs were among the first compounds shown to be effective against viral infections. The pioneering work of Elion and colleagues at Burroughs-Wellcome led to the development of acyclovir which is used extensively in the treatment of herpetic infections (1). Therefore, it is not surprising that the first four anti-HIV drugs to be approved, AZT, ddI, ddC and D4T ; were nucleoside analogs. All four of these drugs and other nucleoside analogs are believed to have a similar mechanism of HIV inhibition, in which the nucleosides are progressively phosphorylated to a 5'-triphosphate, which then acts as a chain terminator in a reverse transcriptase (RT) reaction.

Anti-HIV activity is dependent on the intracellular phosphorylation of the analog and the ability of the phosphorylated analog to interact with the HIV-RT. The rate limiting step in most cells is believed to be the initial phosphorylation by nucleoside kinases, or in the case of AZT, the conversion of a nucleoside monophosphate to a nucleoside diphosphate. Many 2'-3' dideoxynucleoside analogs have potent inhibitory effects on viral RT when in the triphosphate form, but little effect as a nucleoside on HIV infected cells. This lack of activity is believed to be due to low affinity between the nucleoside or nucleotide analog and cellular kinases, such as thymidine kinase. Nucleoside kinase and nucleotide kinase activity varies widely between cells. Some HIV-infectable cells, such as monocytes and macrophages, when at rest, are believed to have little kinase activity. This could account for the inability of AZT and other nucleoside analogs to prevent transmission when given immediately after HIV exposure. Prodrugs such as methoxyglycinyl derivatives and bis[S-(2-hydroxyethylsulfidyl)-2-thioethyl] esters have been designed to form monophosphorylated nucleoside analogs intracellularly. Acyclic nucleoside phosphonates, such as 9-(2-phosphonylmethoxyethyl)adenine (PMEA), have also been used to overcome the kinase bottleneck. The acyclic phosphonate analog, 9-(2-phosphonylmethoxypropyl)adenine (PMPA) has been reported to prevent SIV transmission in macaques, even when administered 24 hours after exposure (2).

Another approach to increase the potency of nucleoside analogs has been to use potentiating drugs to increase the amount of dideoxynucleoside triphosphates and decrease the amount of deoxynucleoside triphosphates. Ribavirin and hydroxyurea have been shown to enhance the anti-HIV activity of ddI by suppressing the formation of dATP and facilitating the conversion of ddI to ddATP without increasing the toxicity of ddI.

The major limitations of nucleoside analogs include their toxicity, lack of activity in some cell types, and susceptibility to viral resistance. Toxic side effects vary from compound to compound: anemia and/or neutropenia are frequently seen with AZT; neutropenia and peripheral neuropathy with 3TC; peripheral neuropathy with ddC , D4T and ddI; and acute pancreatitis with ddI. HIV viral isolates from patients are often resistant to the nucleoside analog that was used therapeutically in the patient. Resistance has also been reported in patients who have not been treated with nucleoside analogs.

The mutations responsible for viral resistance to nucleoside analogs have all been mapped to the RT enzyme. The five following mutations in HIV-1 RT, confer a high level of resistance to AZT: 41 Met--Leu; 67 Asp--Asn; 70 Lys--Arg; 215 Thr--Phe/Tyr; 219 Lys--Gln. Multiple mutations in RT have also been reported to occur in an ordered fashion, such as: 41--41/215--41/67/215--41/67/70/215--41/67/70/215/219; with each mutation leading to accrued resistance. Although extensive structural and genetic studies have been done on AZT resistant enzymes, a biochemical explanation for AZT resistance is still lacking. Most AZT-resistant enzymes bind AZT-triphosphate with the same avidity as nonresistant enzymes. Resistance to ddI is conferred by the 74 Leu--Val mutation, the 69 Thr--Asp mutation reduces susceptibility to ddC ; the 75 Val--Thr mutation confers resistance to D4T . The 184 Met--Val mutation not only confers multiple resistance to ddC , 3TC and ddI, but also will supress the effects of AZT resistant mutations resulting in an enzyme that is once again susceptible to AZT. Enzymes containing the 184 Met--Val mutation also makes 50-fold less errors compared to the wild-type enzyme. This increased fidelity that results from 3TC resistance, should also reduce the appearance of protease resistant strains. Currently, many treatment regimens consist of two nucleoside analogs (i.e. AZT and 3TC), and a protease inhibitor. These treatments are designed to lead to the greatest reduction in viral burden and also to prevent protease resistant strains from appearing (3).

Nucleoside analogs will continue to play a major role in anti-HIV therapy, current efforts are underway to develop analogs that are less toxic, less susceptible to viral resistance and less dependent on kinases whose activity varies from cell to cell. Nucleoside analogs less susceptible to resistance and effective in a wider variety of cells could play a major role in achieving HIV viral eradication and in preventing initial HIV infection.

Approved Nucleoside Analogs

• AZT
• 3TC
• ddI
• ddC
• D4T
• Abacavir Succinate

References

1. ELION, G.E, FURMAN, P.A., FYFE, J.A., DEMIRANDA P., BEAUCHAMP, L., SCHAEFFER H.J., SELECTIVITY OF ACTION OF AN ANTIHERPETIC AGENT, 9-(2-HYDROXYETHOXYMETHYL) GUANINE. PROC. NATL. SCI. USA, 74:5716-5721 (1977).

2. TSAI, C-C., FOLLIS, K.E., SABO, ET AL., PREVENTATION OF SIV INFECTION IN MACAQUES BY (R)- 9-(2-PHOSPHONYLMETHOXYPROPYL)ADENINE. SCIENCE 270:1194-1197 (1995).

3. ERICKSON, J.W., BURT, S.K. STRUCTURAL MECHANISMS OF HIV DRUG RESISTANCE. ANNU. REV. PHARMACOL. TOXICOL. 36:545-71 (1996).