Immucillins in Infectious Diseases
#MMPMID29151351
Evans GB
; Tyler PC
; Schramm VL
ACS Infect Dis
2018[Feb]; 4
(2
): 107-117
PMID29151351
show ga
The Immucillins are chemically stable analogues that mimic the ribocation and
leaving-group features of N-ribosyltransferase transition states. Infectious
disease agents often rely on ribosyltransferase chemistry in pathways involving
precursor synthesis for nucleic acids, salvage of nucleic acid precursors, or
synthetic pathways with nucleoside intermediates. Here, we review three
infectious agents and the use of the Immucillins to taget enzymes essential to
the parasites. First, DADMe-Immucillin-G is a purine nucleoside phosphorylase
(PNP) inhibitor that blocks purine salvage and shows clinical potential for
treatment for the malaria parasite Plasmodium falciparum, a purine auxotroph
requiring hypoxanthine for purine nucleotide synthesis. Inhibition of the PNPs in
the host and in parasite cells leads to apurinic starvation and death. Second,
Helicobacter pylori, a causative agent of human ulcers, synthesizes menaquinone,
an essential electron transfer agent, in a pathway requiring aminofutalosine
nucleoside hydrolysis. Inhibitors of the H. pylori methylthioadenosine
nucleosidase (MTAN) are powerful antibiotics for this organism. Synthesis of
menaquinone by the aminofutalosine pathway does not occur in most bacteria
populating the human gut microbiome. Thus, MTAN inhibitors provide
high-specificity antibiotics for H. pylori and are not expected to disrupt the
normal gut bacterial flora. Third, Immucillin-A was designed as a transition
state analogue of the atypical PNP from Trichomonas vaginalis. In antiviral
screens, Immucillin-A was shown to act as a prodrug. It is active against
filoviruses and flaviviruses. In virus-infected cells, Immucillin-A is converted
to the triphosphate, is incorporated into the viral transcript, and functions as
an atypical chain-terminator for RNA-dependent RNA polymerases. Immucillin-A has
entered clinical trials for use as an antiviral. We also summarize other
Immucillins that have been characterized in successful clinical trials for T-cell
lymphoma and gout. The human trials support the potential development of the
Immucillins in infectious diseases.
|Anti-Infective Agents/chemistry/*pharmacology/*therapeutic use
[MESH]
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