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The kinetic properties of switch antimetabolites
1Agouron Pharmaceuticals, Inc., San Diego, CA 92121.
Background:
Maintaining homeostasis is the biological function of negative feedback, a process that plays a well-understood role in the biochemistry of antimetabolite drugs. An equally important property of living systems--the ability to respond to external stimuli by switching rapidly from one state to another--is mediated by positive feedback. Kinetic analysis of multi-enzyme biochemical pathways has shown that pathways containing positive feedback coupled with negative feedback may act as biochemical switching systems in which multiple steady states are possible.
Purpose:
A computer model was used to study the kinetic effects of antimetabolites that inhibit biochemical pathways at positive feedback sites and to determine whether the kinetics of such systems differed from those of classical antimetabolites.
Methods:
Kinetics were simulated by microcomputer to model the effects of inhibitors on a simplified metabolic pathway.
Results:
Antimetabolite drugs that act at positive feedback sites are predicted to display highly nonclassical properties. Three nonclassical properties are kinetically possible. First, the drugs may switch off the pathway at substoichiometric concentrations; classical antimetabolites require stoichiometric levels and sometimes much more. Second, instead of demonstrating classical continuous inhibition, antimetabolite drugs that act at positive feedback sites may give "all-or-none" dose-response curves with discontinuity at a specific value. Inhibitor concentrations below this value would have no overall effect on the system, while inhibitor concentrations at or above this value would give an abrupt transition to an inhibited steady state. Third, the inhibited system may show hysteresis and remain switched off after the inhibitor is removed.
Conclusions:
These findings suggest that antimetabolites acting at switch points could have kinetic properties very different from those of classical antimetabolites and could provide a noncytotoxic method of switching off pathways in neoplastic cells, perhaps leading to cell stasis.
Implications:
Experimental validation of these conclusions will require identification of the positive feedback sites of metabolic and signaling pathways and exploration of the effects of inhibitors of these sites. The properties of "switch antimetabolites" should prompt a search for new kinds of targets for drug design.
Insights
New antimetabolite drugs targeting positive feedback sites may offer novel ways to control biochemical pathways. These "switch antimetabolites" could offer noncytotoxic therapeutic strategies by rapidly altering cellular states.
Area of Science:
- Biochemistry
- Systems Biology
- Pharmacology
Background:
- Homeostasis relies on negative feedback, while positive feedback enables rapid state transitions in biological systems.
- Multi-enzyme pathways with both positive and negative feedback can function as biochemical switches with multiple stable states.
Purpose of the Study:
- To investigate the kinetic effects of antimetabolites inhibiting positive feedback sites in biochemical pathways.
- To compare the kinetics of these novel antimetabolites with classical antimetabolites.
Main Methods:
- Computer simulations were employed to model a simplified metabolic pathway.
- The effects of inhibitors acting at positive feedback sites were kinetically simulated.
Main Results:
- Antimetabolites acting at positive feedback sites exhibit nonclassical properties, including pathway switching at substoichiometric concentrations.
- These drugs can induce 'all-or-none' dose-response curves, with abrupt inhibition above a specific threshold.
- Inhibited systems may display hysteresis, remaining switched off after inhibitor removal.
Conclusions:
- Antimetabolites targeting positive feedback sites possess distinct kinetic properties compared to classical inhibitors.
- These 'switch antimetabolites' present a potential noncytotoxic strategy for inhibiting pathways in neoplastic cells, potentially inducing cell stasis.
- Further research should identify positive feedback sites and explore inhibitors, guiding the design of novel drug targets.