HEPT derivatives are nucleoside analogues the family of anti-HIV drugs to which AZT (zidovudine, Retrovir), ddI (didanosine, Videx / VidexEC) and ddC (zalcitabine, Hivid) also belong. These drugs act by inhibiting HIV's reverse transcriptase enzyme, but HEPT derivatives seem to inhibit the enzyme in a different way from AZT, ddI and ddC. Their mechanism of action may be similar to that of the non-nucleoside reverse transcriptase inhibitors such as efavirenz (Sustiva) and nevirapine (Viramune).

Current use

HEPT derivatives are unlicensed, experimental drugs which have not yet been tested in humans. Test-tube results suggest that the compounds may be effective against AZT-resistant virus and are unlikely to harm the bone marrow as AZT can.

Key research

HEPT derivatives are a series of acyclouridine derivatives with substitutions at the C-6 position. They appear to inhibit HIV-1 through direct interaction with the HIV reverse transcriptase. They do not require phosphorylation to exhibit anti-HIV activity and they do not inhibit HIV-2 or any other retroviruses. The investigators speculate that the HEPT derivatives have a common mechanism of action with the benzodiazepine derivatives TIBO/TIBOL compounds and BI-RG-587.

Baba (1990) reported that in vitro, HEPT and its analogue HEPT-S inhibited HIV-1 replication by 50% in MT-4 cells at concentrations of 6.5 and 1.6 mM respectively and inhibited cell viability by 50% at 740 mM. Ito reported that in vitro HEPT and interferon alfa synergistically inhibit HIV-1 replication.

Baba (1991a) and Tanaka have since reported on new 5-ethyl derivatives with in vitro anti-HIV-1 activity in the nanomolar range. The IC₅₀s for one such compound (E-EBU-dM,5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)ur-acil) were 2.2 and 0.45 nM in MT-4 cells and PBL, respectively. These concentrations were more than 100,000 times less than the 50% cytotoxic concentration. E-EBU-dM specifically acted on the HIV-1 reverse transcriptase. These derivatives are active in vitro against clinical AZT-resistant HIV-1 isolates. Baba (1991b) reported that in vitro the 5-ethyl derivative E-EPU and AZT synergistically inhibit HIV-1 replication.

Baba (1993) found that although all HEPT derivatives proved to be highly potent inhibitors of HIV-1 in the presence of 10% fetal bovine serum, some of them were less inhibitory to HIV-1 replication in the presence of human serum. The HEPT derivatives were found to be highly bound to human serum proteins. Both the anti-HIV-1 activity and human serum protein binding of the compounds appeared to be related to their lipophilicity.

The pharmacokinetic behaviour of HEPT derivatives was studied in rats. The drug was about 40% bioavailable. A dose of 20 mg/kg resulted in a mean plasma drug concentration of 22.8 mM, the LD₅₀ was greater than 2000 mg/kg.

HEPT in vitro did not harm bone marrow cells at concentrations 20 times greater than that at which AZT is significantly toxic. HEPT was not inhibitory to T-lymphoblast MOLT/4F cell proliferation at the same concentration.

References

Baba M et al. Anti-human immunodeficiency virus type 1 activities and pharmacokinetics of novel 6-substituted acyclouridine derivatives. Antimicrobial Agents & Chemotherapy 34(12):2358-2363, 1990.

Baba M et al. Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase. PNAS USA 88:2356-2360, 1991a.

Baba M et al. Synergistic inhibition of human immunodeficiency virus type 1 replication by 5-ethyl-1-ethoxymethyl-6-(phenylthio) uracil (E-EPU) and azidothymidine in vitro. Antimicrobial Agents & Chemotherapy 35(7):1430-1433, 1991b.

Baba M et al. Effect of human serum on the in vitro anti-HIV-1 activity of 1-[(2 -hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) derivatives as related to their lipophilicity and serum protein binding. Biochem Pharmacol 45(12):2507-2512, 1993.

Ito M et al. Synergistic inhibition of human immunodeficiency virus type 1 (HIV-1) replication in vitro by HEPT and recombinant alpha interferon. Antivir Res 15(4):323-330, 1991.

Tanaka H et al. A new class of HIV-1 specific 6-substituted acyclouridine derivatives: synthesis and anti HIV-1 activity of 5-or 6- substituted analogs of 1-[2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). J Med Chem 34(1):349-357, 1991.