Avermectin Derivatives Inhibit P-glycoprotein Efflux
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Solution Overview
Problem
The widespread resistance of nematode parasites to macrocyclic lactones, such as avermectins, due to the expression of multidrug resistance transporters like P-glycoprotein, limits the efficacy of these drugs in treating parasitic infections, and existing inhibitors face toxicity issues, necessitating the development of safer and more effective inhibitors.
Innovation Solution
Avermectin derivatives, specifically aglycone and monosaccharide forms, are developed as inhibitors of membrane-bound proteins like P-glycoprotein, offering comparable or higher inhibitory potency to known inhibitors like Valspodar while exhibiting reduced neurotoxicity, thereby enhancing the bioavailability of active ingredients by blocking efflux pumps.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If macrocyclic lactones are used to treat parasitic infections, then anti-parasitic efficacy is achieved, but drug resistance develops due to MDR transporter expression
Solution Approach 1:
The patent uses MDR transporter inhibitors as intermediary substances that block the efflux pump mechanism. These inhibitors bind to P-glycoprotein and other MDR transporters, preventing them from pumping macrocyclic lactones out of parasite cells, thereby maintaining intracellular drug concentrations and restoring anti-parasitic efficacy despite resistance development
Solution Approach 2:
The patent modifies the chemical parameters of macrocyclic lactones by creating derivatives with altered molecular structures that have reduced affinity for MDR transporters. This parameter change in the drug molecule itself allows it to evade the efflux mechanism without losing its anti-parasitic activity
2Quantity of substance
If MDR transporter inhibitors are used to overcome resistance, then drug bioavailability increases, but toxicity increases
Solution Approach 1:
The patent applies local quality by designing MDR transporter inhibitors with selective binding properties that target parasite MDR transporters while sparing mammalian cells. The inhibitors exhibit different molecular characteristics that allow them to interact preferentially with nematode P-glycoprotein rather than human transporters, reducing off-target toxicity
Solution Approach 2:
The patent creates simplified analogs and derivatives that copy the essential inhibitory function of complex MDR inhibitors like verapamil but with reduced side effects. These simplified structures maintain the key pharmacophore elements needed for transporter binding while removing or modifying groups responsible for toxic effects
3Reliability
If existing MDR inhibitors like verapamil are used, then efflux pump inhibition is achieved, but neurotoxicity and other side effects occur
Solution Approach 1:
The patent extracts and isolates the specific pharmacophore elements responsible for MDR transporter binding from complex inhibitor molecules. By taking out only the essential binding moieties and removing other functional groups, the patent creates minimal structures that retain efflux pump inhibition capability while eliminating neurotoxic properties
Solution Approach 2:
The patent develops simple, small-molecule inhibitors that are structurally simpler and potentially more metabolizable than complex inhibitors like verapamil. These simplified structures may be processed and eliminated more readily by biological systems, reducing accumulation and associated neurotoxicity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These avermectin derivatives effectively inhibit multidrug resistance proteins, particularly nematode P-glycoprotein, improving the intracellular concentration of drugs and reversing resistance in parasites and cancer cells, with reduced toxicity and improved therapeutic efficacy.
Implementation Method 1
Pgp can transport its substrate from the baso-lateral side to the apical side of epithelia and endothelia. MDR transporters are membrane proteins belonging to the ABC (ATP binding cassette) family, and whose main function is the ATP-dependent transport of a number of structurally unrelated exogenous compounds.
Implementation Method 2
The principal action of MLs in parasitic nematodes is to increase membrane permeability to chloride ions by interacting with the glutamate-gated chloride channel subunit.
Data Source
AI summary
The present invention relates to the use of avermectin derivative as a drug for the treatment of parasitic infections. The avermectin derivative is represented by the formula (I) wherein: (i) R1 is chosen from the group constituted of —CH(CH3)2, —CH(CH3)CH2CH3, or cyclohexyle, (ii) X represents —CH2—CH2—, or —CH═CH—, (iii) R2 is chosen from the group constituted of or —OH group, (iv) R3 is OH or NOH, (v) represents a single bond when R3 is OH, or a double bond when R3 is NOH, as an inhibitor of a membrane-bound protein which transports exogenous compounds out of target cells.