Abacavir and Mycophenolic Acid, an Inhibitor of Inosine Monophosphate Dehydrogenase, Have Profound and Synergistic Anti-HIV Activity

Heredia, Alonso; Gaywee, Jariyanart; Oldach, David; Drusano, George L.; Redfield, Robert

doi:10.1097/00042560-199908150-00002

Cited by 49 publications

(6 citation statements)

References 29 publications

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“…Micophenolic acid inhibits the enzyme inosine monophosphate dehydrogenase, limiting the de novo synthesis of deoxyguanosine triphosphate (dGTP) [45,46] and inhibiting HIV replication by guanine depletion [47]. Micophenolic acid has been shown to increase the potency of abacavir, didanosine and tenofovir both in vitro [48][49][50] and in vivo [51][52][53][54]. Leflunomide inhibits the de novo activity of dihydroorotic acid dehydrogenase, therefore inhibiting pyrimidine synthesis [55].…”

Section: Dose Finding Studies Of Hydroxyurea-didanosine Combinationmentioning

confidence: 99%

Virostatics: A New Class of Anti-HIV Drugs

Friedman¹,

Foli²,

Kelly³

et al. 2007

CMC

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In this review we discuss the features of a new class of antiretroviral combinations, namely "Virostatics". Virostatics are characterized by the combination of a drug directly inhibiting virus production (viro), and another drug indirectly inhibiting the virus by reducing cellular proliferation (static). In particular, we will focus on the combination of hydroxyurea and didanosine against HIV-1. Hydroxyurea and didanosine synergize to control viral replication and present with a favorable resistance profile, suppressing several resistant quasi-species. Because virostatics target essential cellular proteins, they exert an immune modulating activity and reduce viral targets (CD4 T cells), possibly with limited immunosuppressive effects. Importantly, a dose-finding clinical study has shown that decreasing the dose of hydroxyurea not only diminishes toxicity but also increases antiviral potency. Therefore, the combination of hydroxyurea and didanosine strikes a balance between viral suppression, drug-related toxicity and viral escape, and could have a role both in induction and maintenance therapy. In this review we would like to appraise what is known about hydroxyurea and didanosine and specifically address the major advantages, i.e. novel mechanism of action leading to a new class of drugs and resistance profile providing durability, as well as the major criticisms of this combination, i.e. toxicity and reasons for prescribing a perceived immune suppressant to immune compromised patients.

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Section: Dose Finding Studies Of Hydroxyurea-didanosine Combinationmentioning

confidence: 99%

Virostatics: A New Class of Anti-HIV Drugs

Friedman¹,

Foli²,

Kelly³

et al. 2007

CMC

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“…174 Recent publications have concerned the experimental use of MMF in the following situations with promising results being recorded in each case: Systemic lupus erythematosus, 163 lupus nephritis refractory to cyclophosphamide, 175 myasthenia gravis, 176 inflammatory eye disease, 177 autoimmune and inflammatory skin disorders 178,179 (including psoriasisssee earlier material on use of MPA itself for this condition), and glomerular disease. 180 MMF blocks replication of HIV in lymphocytes, 181 has a profound and synergistic anti-HIV activity in combination with abacavir, 182 and is active against multidrug-resistant HIV-1. 183 As for many medications, there are limitations to the use of MMF and certain side effects; the most common are diarrhea, leukopenia, sepsis, and vomiting.…”

Section: Mycophenolate Mofetil a Prodrugmentioning

confidence: 99%

Mycophenolic Acid: A One Hundred Year Odyssey from Antibiotic to Immunosuppressant

2000

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“…The estimated IC 50 of MMF against COX-2 was 0.19 µM, far below the clinically attainable MPA (1-10 µM) (Margolis et al, 1999). This result indicates that the COX-2 inhibitory activity can be attained during the clinical use of MMF.…”

Section: Discussionmentioning

confidence: 83%

“…MMF is a prodrug of mycophenolic acid (MPA), an antimetabolite that inhibits inosine monophosphate dehydrogenase and decreases the recruitment of lymphocytes and monocytes into sites of inflammation (Allison & Eugui, 2000). Due to its antimetabolite activity, MMF and its active form (MPA), either alone or in combination with other antimicrobial agents, demonstrate anti-parasitic and antiviral activity (Allison & Eugui, 2000;Margolis et al, 1999). However, MMF replaced MPA in clinical use after the latter's gastrointestinal side effects were discovered (Park, 2011).…”

Section: Introductionmentioning

confidence: 99%

Mycophenolate suppresses inflammation by inhibiting prostaglandin synthases: a study of molecular and experimental drug repurposing

Al-Hizab

Kandeel

2021

PeerJ

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Mycophenolate mofetil is an established anti-proliferative and immune-suppressive agent that minimizes the proliferation of inflammatory cells by interfering with nucleic acid synthesis. Herein, we report our discovery of the prostaglandin inhibiting properties of MMF, which offers new applications for the drug in the treatment of inflammatory diseases. The estimated values of IC50MMFCOX-1, IC50MMFCOX-2, and IC50MMF5-LOX were 5.53, 0.19, and 4.47 µM, respectively. In contrast, mycophenolic acid (MPA) showed slightly stronger inhibition: IC50MPACOX-1, IC50MPACOX-2, and IC50MPA5-LOX were 4.62, 0.14, and 4.49 µM, respectively. These results indicate that MMF and MPA are, respectively, 28.6 and 33 times more selective for cyclooxygenase-2 than for cyclooxygenase-1, which implies that MMF would have less impact on the gastric mucosa than most nonselective, nonsteroidal anti-inflammatory drugs. Furthermore, MMF provided dose-dependent relief of acute inflammation in the carrageenan-induced rat paw edema test, with results comparable to those of celecoxib and indomethacin. Molecular dynamics simulations indicated that the MMF bond with COX-2 was stable, as evidenced by a low root-mean-square deviation of atomic positions, complementary per-residue root-mean-square fluctuation, and 0–4 hydrogen bonds during the 50-ns simulation time. Therefore, MMF provides immune-suppressing, cyclooxygenase-inhibiting, and inflammation-relieving properties. Our results indicate that MMF can be 1) repositioned for inflammation treatment without the need for further expensive clinical trials, 2) used for local acute inflammations, and 3) used as a sparing agent for other steroid and non-steroid anti-inflammatory medications, especially in topical applications.

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Abacavir and Mycophenolic Acid, an Inhibitor of Inosine Monophosphate Dehydrogenase, Have Profound and Synergistic Anti-HIV Activity

Cited by 49 publications

References 29 publications

Virostatics: A New Class of Anti-HIV Drugs

Virostatics: A New Class of Anti-HIV Drugs

Mycophenolic Acid: A One Hundred Year Odyssey from Antibiotic to Immunosuppressant

Mycophenolate suppresses inflammation by inhibiting prostaglandin synthases: a study of molecular and experimental drug repurposing

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