Nuclear Magnetic Resonance and Molecular Modeling Study on Mycophenolic Acid:  Implications for Binding to Inosine Monophosphate Dehydrogenase

1996 ◽  
Vol 39 (6) ◽  
pp. 1236-1242 ◽  
Author(s):  
Gergely M. Makara ◽  
György M. Keserû ◽  
Mária Kajtár-Peredy ◽  
Wayne K. Anderson
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Molecular Modeling ◽  
Magnetic Resonance ◽  
Mycophenolic Acid ◽  
Inosine Monophosphate Dehydrogenase ◽  
Inosine Monophosphate ◽  
Molecular Modeling Study ◽  
Modeling Study ◽  
Nuclear Magnetic ◽  
Monophosphate Dehydrogenase

Threading Bis-Intercalation of a Macrocyclic Bisacridine at Abasic Sites in DNA: Nuclear Magnetic Resonance and Molecular Modeling Study†

Biochemistry ◽  
1999 ◽  
Vol 38 (43) ◽  
pp. 14205-14213 ◽  
Author(s):  
Muriel Jourdan ◽  
Julian Garcia ◽  
Jean Lhomme ◽  
Marie-Paule Teulade-Fichou ◽  
Jean-Pierre Vigneron ◽  
...  
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Molecular Modeling ◽  
Magnetic Resonance ◽  
Abasic Sites ◽  
Molecular Modeling Study ◽  
Modeling Study ◽  
Nuclear Magnetic

scholarly journals In Vitro Combination of Amdoxovir and the Inosine Monophosphate Dehydrogenase Inhibitors Mycophenolic Acid and Ribavirin Demonstrates Potent Activity against Wild-Type and Drug-Resistant Variants of Human Immunodeficiency Virus Type 1

2004 ◽  
Vol 48 (11) ◽  
pp. 4387-4394 ◽  
Author(s):  
Katyna Borroto-Esoda ◽  
Florence Myrick ◽  
Joy Feng ◽  
Jerry Jeffrey ◽  
Phillip Furman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mycophenolic Acid ◽  
Inosine Monophosphate Dehydrogenase ◽  
Wild Type ◽  
Inosine Monophosphate ◽  
Immunodeficiency Virus ◽  
Monophosphate Dehydrogenase

ABSTRACT Amdoxovir [(−)-β-d-2,6-diaminopurine dioxolane (DAPD)] is a nucleoside analogue reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. DAPD is deaminated by adenosine deaminase to the guanosine analogue dioxolane guanosine (DXG), which is subsequently phosphorylated to the corresponding 5′ triphosphate (DXG-TP). DXG-TP competes with the natural substrate dGTP for binding to the enzyme-nucleic acid complex. Mycophenolic acid (MPA) and ribavirin (RBV), inhibitors of inosine monophosphate dehydrogenase (IMPDH), inhibit the de novo synthesis of guanine nucleotides, including dGTP. Reducing the intracellular levels of dGTP would be expected to augment the antiviral activity of analogues of deoxyguanosine. In this study we examined the effect of MPA and RBV on the anti-HIV activity of DAPD and DXG. When tested against wild-type virus, both MPA and RBV decreased the 50% effective concentration (EC50) for DXG by at least 10-fold. In contrast, both MPA and RBV increase the EC50 value for zidovudine. MPA and RBV completely reversed the resistance to DXG observed with HIV isolates containing mutations which confer partial resistance to DAPD and DXG. Similarly, when tested against a mutant virus fully resistant to inhibition by DAPD (K65R/Q151M), MPA and RBV reduced the EC50 for DAPD to within twofold of that for the wild type. The combination of MPA or RBV with DAPD or DXG did not result in increased cytotoxicity or reduced levels of mitochondrial DNA when tested at physiologically relevant concentrations. These studies suggest a potential role for the use of IMPDH inhibitors in combination therapy with amdoxovir in the treatment of HIV.

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