Amdoxovir is a guanosine analogue nucleoside reverse transcriptase inhibitor that is active in vitro against both HIV-1 and HBV. It is deaminated intracellularly by adenosine deaminase to dioxolane guanine (DXG). DXG-triphosphate, the active form of the drug, has greater activity than DAPD-triphosphate. Amdoxovir is under development (phase II study) for the treatment of HIV infection. Five subjects demonstrated lens opacities during the study, although baseline evaluations were not performed. Clinical studies of amdoxovir are currently on hold pending additional safety data.

Alovudine (3’ -deoxy-3’ fluorothymidine) is a nucleoside reverse transcriptase inhibitor (NRTI) initially tested in the early 1990s, before the era of combination therapy and before the availability of plasma viral load measurement. Initial toxicity studies showed that the primary target organ of toxicity was the bone marrow. A lack of clear advantages in activity over zidovudine, the only drug approved in the early 1990s, and the potential for bone marrow toxicity caused alovudine development to be stopped [6]. However, later in vitro studies found alovudine to be very effective at suppressing several NRTI-resistant HIV-1 mutants, including isolates with multiple thymidine-associated mutations (TAMs) or multi-NRTI-resistance mutations. Alovudine at a dose of 7.5 mg/day added to a failing antiretroviral combined regimen in patients with isolates resistant to other NRTIs yielded a median viral load decline after a 4-week period in patients not receiving concomitant stavudine. In July 2003, Medivir out-licensed it's HIV antiviral MIV-310 to Boehringer Ingelheim. Under the terms of the agreement, Boehringer Ingelheim will make upfront and milestone payments to Medivir totaling up to 122 million euro in the event that all development and performance milestones are met. In March 2005, Boehringer Ingelheim recently completed a clinical trial of MIV-310 (alovudine) in HIV/AIDS. The efficacy exhibited by MIV-310 at the doses tested showed antiviral activity but did not achieve the target level of efficacy which had previously been defined. Boehringer Ingelheim, therefore, decided to stop the development of this investigational drug.

MIV-150 is a tight-binding, allosteric inhibitor of reverse transcriptase that is active against HIV-1 and HIV-2. MIV-150 has been shown to inactivate viruses that are resistant to other antiviral drugs, including non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors. MIV-150 effectively inactivated free virus. Combination of MIV-150 and Carraguard demonstrated an additive antiviral effect. Seminal fluid had no effect on the antiviral activity of MIV-150 or Carraguard. The average concentration that blocks 50% of infection (EC50) for PC-815 was approximately 10 times stronger than Carraguard for the different clinical isolates used in the study.

Fozivudine tidoxil is a thioether lipid–Zidovudine (ZDV) conjugate. After intake it is split intracellularly into the lipid moiety and ZDV-monophosphate, which is subsequently phosphorylated to the active metabolite ZDV-triphosphate. The rationale behind the development of fozivudine (FZD) was to take advantage of the high cleavage activity in mononuclear cells and other organs resulting in increased amounts of intracellular ZDV available for phosphorylation to the active metabolite, and a very low activity in red blood and stem cells, which should result in reduced haematologic toxicity. It is member of the family of nucleoside reverse transcriptase (RT) inhibitors. Fozivudine tidoxil has been in Phase II clinical trials for the treatment of HIV infection. There were three adverse events possibly related to fozivudine: urine abnormality, gastrointestinal pain and abnormal dreams.

Apricitabine (ATC) is an investigational drug that was being studied for the treatment of HIV infection. Apricitabine belongs to a class (group) of HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs block an HIV reverse transcriptase. By blocking reverse transcriptase, NRTIs prevent HIV from multiplying and can reduce the amount of HIV in the body. In vitro studies have shown that apricitabine appears to work on certain HIV strains against which other FDA-approved NRTIs, such as lamivudine (brand name: Epivir), may no longer work. Apricitabine shows antiviral activity in vitro against HIV-1 strains and clinical isolates with mutations in the reverse transcriptase that confer resistance to other NRTIs, including M184V, thymidine analogue mutations (TAMs), nucleoside-associated mutations such as L74V and certain mutations at codon 69. Apricitabine has shown activity in treatment-experienced HIV-1-infected patients with NRTI resistance (with M184V and up to five TAMs) as well as in treatment-naive patients. The study of apricitabine as an HIV medicine was discontinued in 2016. The company developing the drug decided to stop their clinical trials due to a lack of funding and a lack of interest in apricitabine’s early access program.

MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil) is a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Emivirine structurally is a nucleoside analog (NRTI) molecule, but it functions as a non-nucleoside reverse transcriptase inhibitor (NNRTI). Emivirine had reached phase 3 clinical trials for the treatment of HIV-1 infections before its further development was stopped.

Nervonic acid is a long chain unsaturated fatty acid that is enriched in sphingomyelin. It consists of choline, sphingosine, phosphoric acid, and fatty acid. Nervonic acid may enhance the brain functions and prevent demyelination (Chemical Land21). Research shows that there is negative relationship between nervonic acid and obesity-related risk factors. Demyelination in adrenoleukodystrophy (ALD) is associated with an accumulation of very long chain saturated fatty acids stemming from a genetic defect in the peroxisomal beta oxidation system responsible for the chain shortening of these fatty acids. Sphingolipids from post mortem ALD brain have decreased levels of nervonic acid, 24:1(n-9), and increased levels of stearic acid, 18:0. Nervonic acid (C24:1), a component of membrane sphingolipids and phosphatidylethanolamines, may be a useful predictor of chronic kidney disease mortality and diabetes. Nervonic acid oils are being studied for pharmaceutical, nutraceutical and industrial applications. Nervonic acid is a major component of Lunaria oil. There is increasing evidence that dietary supplementation with nervonic acid is healthy for babies and infants during the early stage of brain development. Nervonic acid has been reported to reduce the shaking associated with Parkinson’s disease and the numbness caused by multiple sclerosis. It also has potential for treating schizophrenia and reducing early Alzheimer’s symptoms.

Vitexilactone is a new diterpene from Vitex cannabifolia, V. cannabinifolia, V. trifolia and Tinospora rumphii. This plant is known well as a treatment for HIV-AIDS and shown anti HIV-1 RT activities. Vitexilactone has shown anti HIV activities. Vitexilactone dramatically induced apoptosis both on tsFT210 and K562 cells at higher concentrations while at lower concentrations they inhibited the cell cycle progression of both tsFT210 and K562 cells at the G0/G1 phase.

Nomilin is a limonoid/triterpenoid found in citrus fruits that exhibits anti-parasitic, antiviral, anticancer, anti-metastatic, anti-angiogenic, anti-inflammatory, immunomodulatory, anti-obesity, anti-diabetic, and antiviral activities. Nomilin prevents growth of Aedes and suppresses replication of HIV-1 by inhibiting HIV-1 protease. In animal models, nomilin induces phase II enzymes by increasing expression of glutathione-S-transferase and NADPH:Quinone reductase. In animals fed high fat diets, nomilin activates GR5, increases glucose tolerance, and decreases body weight, glucose levels, and insulin levels. In vivo, nomilin increases white blood cell counts and antibody titers but suppresses delayed-type hypersensitivity reactions. In vitro, this compound inhibits cell proliferation, migration, invasion, and capillary tube formation and decreases levels of IL-1β, IL-6, TNF-α, VEGF, NO, and GM-CSF. Additionally, nomilin also inhibits aromatase and cellular proliferation in breast cancer cells. Nomilin also inhibits osteoclastogenesis in vitro by suppression of NFATc1 and MAPK signaling pathways. Nomilin inhibits tumor-specific angiogenesis by downregulating VEGF, NO and proinflammatory cytokine profile and also by inhibiting the activation of MMP-2 and MMP-9.