US20160003805A1 - Methods for identifying arthropod repellents and attractants, and compounds and compositions identified by such methods - Google Patents

Methods for identifying arthropod repellents and attractants, and compounds and compositions identified by such methods Download PDF

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US20160003805A1
US20160003805A1 US14/855,024 US201514855024A US2016003805A1 US 20160003805 A1 US20160003805 A1 US 20160003805A1 US 201514855024 A US201514855024 A US 201514855024A US 2016003805 A1 US2016003805 A1 US 2016003805A1
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neuron
odor
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Anandasankar Ray
Sean Michael Boyle
Dyan MACWILLIAM
Genevieve Mitchell TAUXE
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University of California
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University of California
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Priority to US15/851,130 priority patent/US10768168B2/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5058—Neurological cells
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/02—Acyclic compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/06—Oxygen or sulfur directly attached to a cycloaliphatic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/04—Nitrogen directly attached to aliphatic or cycloaliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing aliphatically bound aldehyde or keto groups, or thio analogues thereof; Derivatives thereof, e.g. acetals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/06—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing keto or thioketo groups as part of a ring, e.g. cyclohexanone, quinone; Derivatives thereof, e.g. ketals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical at least one of the bonds to hetero atoms is to nitrogen
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing within the same carbon skeleton a carboxylic group or a thio analogue, or a derivative thereof, and a carbon atom having only two bonds to hetero atoms with at the most one bond to halogen, e.g. keto-carboxylic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
    • A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
    • A01N41/10—Sulfones; Sulfoxides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/08—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/10—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with sulfur as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5032—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on intercellular interactions

Definitions

  • the present disclosure relates generally to the field of arthropod repellents and attractants, and more specifically to methods of identifying such repellents based on affecting the detection of human skin odors in arthropods.
  • Blood-feeding insects such as mosquitoes
  • Insect repellents can be very effective in reducing vectorial capacity by blocking the contact between blood-seeking insects and humans; however, they are seldom used in disease-prone areas of Africa and Asia due to high costs and need for continuous application on skin.
  • DEET N,N-Diethyl-m-toluamide
  • DEET is an example of an insect repellent used in the developed world for more than sixty years.
  • DEET is a solvent capable of melting several forms of plastics, synthetic fabrics, painted and varnished surfaces (Krajick et al., Science, 313: 36, 2006).
  • DEET has been shown to inhibit mammalian cation channels and human acetylcholinesterase, which is also inhibited by carbamate insecticides commonly used in disease endemic areas (Corbel et al., BMC Biol, 7, 2009).
  • mosquito strains with resistance to pyrethroid insecticides the main line of defense against mosquitoes in developing countries, are spreading (Butler et al., Nature, 475: 19, 2011).
  • the other major barrier in developing new repellents is the time and cost of development, which can take more than $30 million and several years to identify new compounds that not only repellent to insects, but are also safe for human use.
  • a method for identifying a compound that is a repellent for at least one arthropod species by:
  • identifying a compound that is a repellent for at least one arthropod species by determining whether or not the candidate compound masks or inhibits the detection of the skin odor by the neuron.
  • the neuron expresses at least one of AgGr22, AgGr23, and AgGr24 in Anopheles gambiae (also called Gr1, Gr2 and Gr3), or any insect orthologs thereof.
  • the skin odor is an individual odorant or the skin odor comprises a plurality of odorants.
  • the neuron is a cpA neuron in maxillary palps of mosquitoes.
  • the neuron is from an arthropod.
  • the neuron is from an insect.
  • the compound that is a repellent for at least one arthropod species is identified by determining whether or not the candidate compound masks or inhibits at least 75% of the detection of the skin odor by the neuron.
  • the compound is identified in an in vitro assay or in vivo assay.
  • the activity of the neuron is measured by one or more electrophysiological parameters, one or more activity imaging parameters, or any combinations thereof.
  • composition that includes one or more compound identified according to any of the methods described above.
  • a sample comprising a neuron, wherein the neuron expresses at least one of Gr1, Gr2, and Gr3, or any orthologs thereof;
  • one or more compounds that each is a repellent for at least one arthropod species wherein the one or more compounds each masks or inhibits the detection of the skin odor by the neuron during or after exposure to the one or more compounds.
  • the skin odor is an individual odorant or the skin odor comprises a plurality of odors.
  • the neuron is a cpA neuron. In certain embodiments, the neuron is from an arthropod. In certain embodiments, the neuron is from an insect. In some embodiments, the one or more compounds each masks or inhibits at least 75% of the detection of the skin odor by the neuron.
  • composition for use as an arthropod repellent that includes two or more compounds selected from the compounds of formulae (Ia), (Va) and (III):
  • R 1 and R 2 are each independently selected from the group consisting H, OH, SH, an optionally substituted aliphatic or hetero-aliphatic group having 1 to 6 carbon atoms, and a cyclic group having 4 to 8 ring carbon atoms; or R 1 and R 2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 3 to 6 ring carbon atoms,
  • R 11 and R 12 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms; or R 11 and R 12 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms,
  • R 5 and R 6 are each independently selected from the group consisting of H, D, a halide, and optionally substituted aliphatic group;
  • R 7 is selected from the group consisting of an optionally substituted aliphatic group
  • R 5 and R 6 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; or
  • R 6 and R 7 can be linked together to form an optionally substituted ring selected from the group consisting of cycloalkenyl, aryl, and heterocycle,
  • the composition includes: i) one or more compounds of formula (Ia); and ii) one or more compounds selected from compounds of formulae (Va) and (III), or any combination thereof.
  • the one or more compounds of formula (Ia) are one or more alkyl 2-oxopropanoates.
  • the one or more alkyl 2-oxopropanoates are selected from the group consisting of ethyl 2-oxopropanoate and methyl 2-oxopropanoate.
  • composition for use an arthropod repellent that includes one or more compounds of formula (XII):
  • W is —NR c R d ;
  • a m is an aliphatic group
  • each A n is independently an aliphatic group
  • each R a , R b , R c and R d is independently H or an aliphatic group
  • each R n is independently H or an aliphatic group
  • x is an integer greater than or equal to 1;
  • x is 0 to 8. In certain embodiments, x is 1 or 2; W is —NR c R d ; each R a , R b , R c , R d , and R n is H; and each A n and A m is independently alkyl.
  • the compound is:
  • composition for use as an arthropod repellent that includes: i) one or more pyruvate inhibitors selected from the compounds of Table A, Group II; and ii) one or more super activators selected from the compound of Table A, Group III.
  • the composition is formulated into a lotion, a cream, a spray, a dust, a vaporizer, a treated mat, a treated outerwear, an oil, a candle, or a wicked apparatus.
  • composition for use as an arthropod attractant that includes two or more of the compounds of formulae (Ia), (Xb), (Xc), and (XIa):
  • R 1 and R 2 are each independently selected from the group consisting H, OH, SH, an optionally substituted aliphatic or hetero-aliphatic group having 1 to 6 carbon atoms, and a cyclic group having 4 to 8 ring carbon atoms; or R 1 and R 2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 3 to 6 ring carbon atoms,
  • R 26 , and R 28 -R 30 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R 26 , and R 28 -R 30 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle,
  • R 26 , and R 28 -R 30 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R 26 and R 28 -R 30 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle,
  • R 31 -R 34 are each independently selected the group consisting of H, D, a halides, and an optionally substituted aliphatic group; and/or two or more of R 31 -R 34 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle,
  • composition for use as an arthropod attractant that includes:
  • one or more compounds selected from thiophene, 1H-pyrrole, hex-5-en-2-one, and methyl 2-methylpropanoate are selected from thiophene, 1H-pyrrole, hex-5-en-2-one, and methyl 2-methylpropanoate.
  • composition for use as an arthropod attractant that includes:
  • the cycloalkanone is a C 4 to C 6 cycloalkanone. In one embodiment, the cycloalkanone is cyclopentanone. In another embodiment, the composition includes cyclopentanone and ethyl acetate.
  • compositions for use as an arthropod attractant that includes two or more compounds selected from Table A, Group I.
  • the composition is used in an arthropod trap.
  • the arthropod trap is suction-based, light-based, electric current-based, or any combination thereof.
  • composition comprising a compound identified according to any one of the methods described above.
  • FIG. 1 a is schematic of the maxillary palp capitate peg sensillum with three ORNs.
  • FIG. 1 e is a graph illustrating A. aegypti cpA responses to representative activating odorants are dose dependent, in which all odorants except CO 2 is dissolved in paraffin oil (PO) at 10 ⁇ 2 except where indicated, and error bars are s.e.m.
  • PO paraffin oil
  • FIG. 2 a is a comparison of chemical structures of butyraldehyde, butyric acid, and butyryl chloride.
  • FIG. 2 b depicts representative cp responses to 0.5-s pulses of indicated odorants after a 3-min pre-exposure to butyryl chloride (10 ⁇ 2 ) (cpA-off) or solvent (sham treatment).
  • FIG. 2 c is a bar graph illustrating the mean odorant-evoked responses of the cpA neuron in cpA-off and sham treated mosquitoes
  • FIG. 2 e is a graph illustrating averaged traces
  • EAG electroantennograph
  • FIG. 2 h is a schematic of wind tunnel assay, where human odor was provided by a dish of glass beads that had been worn in socks for ⁇ 6 hrs (Person 1), and flight behaviour of individual female mosquitoes was recorded for 5 min or until they landed on the beads.
  • FIG. 3 a is a schematic providing an overview of the cheminformatics method used to identify novel cpA ligands from a large untested chemical space.
  • FIG. 3 d depicts representative traces from the A. aegypti cp sensillum to 1-s pulses of 0.15% CO 2 prior to and following a 3-s exposure to either solvent (paraffin oil) or (E)-2-methylbut-2-enal (10 ⁇ 1 ).
  • FIG. 3 e is a graph illustrating the cpA baseline activity in the 1 s prior to each stimulus is elevated following exposure to odorant, where error bars are s.e.m.
  • FIG. 4 f depicts representative traces of repeated 1-s stimuli of cyclopentanone (10 ⁇ 2 ) and 0.15% CO 2 .
  • FIG. 4 g is a schematic of two-choice greenhouse experiments with two counterflow geometry traps, in which mosquitoes were trapped overnight in odorant-baited and solvent (water)-baited traps.
  • PCA principle component analysis
  • FIG. 5 b illustrates the PCA analysis of FIG. 5 a relabeled by chemical functional groups, with circle size representing their cpA activity (right).
  • FIG. 5 c is a hierarchical clustering of odorants that interact with cpA with inter-chemical distances generated from activity-optimized descriptors, and sample structures and associated activity are provided.
  • FIG. 5 d provides an overview of the support vector machine (SVM) integrated pipeline to improve computational prediction of novel CpA ligands.
  • SVM support vector machine
  • FIG. 5 e is a graph illustrating the receiver-operating-characteristic curve (ROC) showing increased predictive accuracy of SVM method (red line) to our previous non-SVM method (black line) using a 5-fold cross-validation.
  • ROC receiver-operating-characteristic curve
  • FIG. 6 is an exemplary model for cpA-mediated host-seeking and odorants that disrupt it, in which inhibitors may be used to block attraction to both CO 2 and skin odor (MASK) and activators may be used as lures for traps (PULL).
  • inhibitors may be used to block attraction to both CO 2 and skin odor (MASK) and activators may be used as lures for traps (PULL).
  • PULL lures for traps
  • FIG. 7 a is a schematic of a human odor delivery system.
  • FIG. 7 b is a schematic of an activation screen.
  • insertion sites for “blank” and “odor cartridges” were spaced 12 cm apart, and flow rates through the stimulus controller were adjusted for each individual preparation. Black arrows indicate switch in airflow during stimulus delivery.
  • FIGS. 8 a - 8 f illustrate an electrophysiological analysis of cpA action potential and spiking activity in response to various stimuli (such as odors).
  • FIG. 9 a illustrates sample traces from repeated stimulus experiments: 1-s pulses of odorant (10-2 in PO except CO 2 ) were repeated every 15 s; temporal dynamics of responses to each pulse of the same odorant were virtually identical and are summarized in FIG. 1 d.
  • FIG. 9 b illustrates sample traces and mean cpA responses to 0.5-s pulses of 0.15% and 0.4% CO2 from cpA-off or sham treated mosquitoes 6, 12, and 24 hours after treatment.
  • FIG. 9 c illustrates averaged traces of EAG responses to 0.5-s stimuli of indicated odorants (10-1 in PO).
  • FIG. 9 e is a schematic of the apparatus used to assay short-range attraction to heat and humidity.
  • FIG. 10 a is a schematic of the wind tunnel used in the wind tunnel assays showing the mosquito release chamber, human foot odor bead stage, and retracted bead cover.
  • FIG. 10 b shows histograms quantifying the number of mosquitoes that took off during the 5-minute assay in each of three experimental conditions. Heights of bars are proportional across all three histograms. X's mark when a mosquito landed on the odor source.
  • FIG. 10 c shows plots where each row indicates flight behavior of each individual mosquito assayed. Shaded areas on each line represent time between when the mosquito left the release cage and when it landed on the beads or the assay ended at 5 min Colors correspond to where the mosquito was located in the wind tunnel (as indicated in FIG. 10 a ) at each moment.
  • FIG. 11 c illustrates that the temporal response profiles elicited by repeated exposures to cyclopentanone are similar to those elicited by CO 2 .
  • Individuals were exposed to 6 repeated 1-s pulses of either 0.15% CO 2 or cyclopentanone (10-2), spaced 20 s apart. Shown are the mean responses (across 4 animals per treatment) for each sequential pulse. Activity was calculated in 100 ms bins for a total of 6 s following the onset of the stimulus. Values were adjusted by subtracting baseline activity measured 5-6 s after each pulse.
  • screening methods for identifying one or more compounds that are repellents for at least one arthropod species may mask or inhibit detection of human skin odor by at least one arthropod species.
  • screening methods for identifying one or more compounds that are attractants for at least one arthropod species are also screening methods for identifying one or more compounds that are attractants for at least one arthropod species.
  • Arthropods are invertebrate animals characterized as having an exoskeleton, a segmented body, and jointed appendages. Arthropods belong to the Phylum Arthropoda under Kingdom Animalia.
  • the Phylum of Arthropoda, or an “arthropod” includes any invertebrate animal from the Classes of Insecta, Arachnida, Diplopoda, Chilopoda, Crustacea, and Xiphosura.
  • arthropod may refer to insects and arachnids that are exoparasitic sanguinivorous feeding pests, including any insect from the Order Diptera, such as mosquitoes, and any arachnid from the Order Ixodida, such as ticks.
  • mosquitoes include Anopheles, Mimomyia, Culiseta, Orthopodomyia, Mansonia, Culex, Schumannia, Aedes, Armigeres, Uranotaenia, Tripteroides, Topomyia, Malaya , and Toxorhynchite .
  • an example of the Anopheles includes anopheles sinesis wiedemann .
  • Examples of the Culex include Culex quinquefasciatus, Culex pipiens pallens, Culex pipiens molestus , and Culex tritaeniorhynchus .
  • Examples of the Aedes include Aedes albopictus and Aedes aegypti .
  • An example of the Armigeres includes Armigeres subalbatus.
  • the screening methods can be used to identify one or more arthropod repellents based on masking or inhibiting the detection of the skin odor by a Gr1-, Gr2- and/or Gr3-expressing neuron (e.g., that may be a cpA neuron).
  • a Gr1-, Gr2- and/or Gr3-expressing neuron e.g., that may be a cpA neuron.
  • the method includes: a) providing a candidate compound and a skin odor; b) providing a sample comprising a Gr1-, Gr2- and/or Gr3-expressing neuron; c) contacting the candidate compound with the sample; d) measuring the detection of the skin odor by the Gr1-, Gr2- and/or Gr3-expressing neuron; e) comparing the detection of the skin odor by the Gr1-, Gr2- and/or Gr3-expressing neuron after contact with the candidate compound to the detection of the skin odor by the Gr1-, Gr2- and/or Gr3-expressing neuron in the absence of the candidate compound; and f) identifying a compound that is a repellent for at least one arthropod species by determining whether or not the candidate compound masks or inhibits the detection of the skin odor by the Gr1-, Gr2- and/or Gr3-expressing neuron.
  • the screening methods can also be used to identify one or more arthropod attractants based on activating a Gr1-, Gr2- and/or Gr3-expressing neuron.
  • the screening methods provided herein may be used to screen one candidate compound or a plurality of candidate compounds.
  • the one or more candidate compounds may be natural or synthetic compounds.
  • the one or more candidate compounds may be from bacterial, fungal, plant and animal extracts that are commercially available or readily produced.
  • the one or more candidate compounds can also be chemically-modified compounds, such as by acylation, alkylation, esterification, or acidification of natural compounds.
  • the one or more candidates compounds screened in the methods described herein may be pre-selected based on one or more criteria. For example, a set of compounds with structural similarities to known insect repellents, like DEET, may be screened and selected for use in the methods described herein. A computation method may be used to select such candidate compounds.
  • Other criteria used for selecting the one or more candidate compounds include the environmental impact of the compounds, regulatory approval of the compounds for human consumption (e.g., FDA-approval), and the smell of the compounds (e.g., natural fragrances, aromas, or odors).
  • the skin odor provided with a candidate compound or plurality of candidate compounds may be an individual odor or a blend of odors.
  • vertebrate odor e.g., human odor
  • Odors that can be found in human skin and that activates the Gr1-, Gr2- and/or Gr3-expressing neuron may include, for example, the compounds in FIG. 1A or any combinations thereof.
  • Vertebrate odor may also include skin odor blend collected from placing an adsorbent or absorbent material in contact with skin, or placed in the headspace above the skin, or a gas passed over the skin, Or skin brought into close vicinity of the cpA.
  • the sample provided in the methods described herein may include a Gr1-, Gr2- and/or Gr3-expressing neuron.
  • the neuron may include three conserved seven-transmembrane domain proteins encoded by members of the gustatory receptor (Gr) gene family (Gr1, Gr2, and/or Gr3 in most mosquitoes, or AgGr22, AgGr23, and AgGr24 in A. gambiae ( FIG. 1 a )).
  • Such neuron may be a cpA neuron, which is an olfactory receptor neuron (ORN), housed in specialized capitate peg (cp) sensilla and express the CO 2 receptor.
  • ORN olfactory receptor neuron
  • cpA neurons are located in the maxillary palp organs. However, the location of cpA neurons in other arthropod species may vary.
  • the neuron may be activated in response to a vertebrate skin odor.
  • the sample includes a cell expressing Gr1, Gr2, Gr3, or a combination thereof.
  • the neurons of the present disclosure may include a Gr1 receptor.
  • Gr1 receptors are known in the art.
  • the Gr1 receptors of the present disclosure may include a Gr1 receptor selected from, for example, Aedes aegypti, Anopheles gambiae, Culex quinquefasciatus, Bombyx mori, Tribolium castenium, Phlebotomus papatasi, Heliconius melpomene, Manduca sexta , and Mayetiola destructor.
  • a homolog or an ortholog or any known or putative Gr1 receptor may also be used in the methods and systems described herein.
  • a homolog may be a protein whose nucleic acid sequence that encodes that protein has a similar sequence to the nucleic acid sequence that encodes a known or putative Gr1 receptor, or a protein whose amino acid sequence is similar to the amino acid sequence of a known or putative Gr1 receptor.
  • Gr1 homologs may have functional, structural or genomic similarities to any known or putative Gr1 receptor.
  • One of skill in the art would recognize the techniques that may be employed to clone homologs of a gene, using genetic probes and PCR.
  • Homologs can also be identified by reference to various databases and identity of cloned sequences as homolog can be confirmed using functional assays and/or by genomic mapping of the genes. Additionally, one of skill in the art would understand that an ortholog is an evolutionarily-related polypeptide or polynucleotide sequence in different species that have similar sequences and functions, and that develop through a speciation event.
  • a homolog and/or ortholog of a Gr1 receptor is a protein whose nucleic acid sequences have at least 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the nucleic acid sequence encoding any known or putative Gr1 receptor.
  • a homolog of a Gr1 receptor is a protein whose amino acid sequence has at least 30%, 40%, 50% 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence encoding any known or putative Gr1 receptor.
  • the Gr1 receptor may be from one or more arthropod species.
  • the Gr1 receptor is a homolog or ortholog of the Gr1 receptor from Aedes aegypti .
  • the Gr1 receptor has at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a polypeptide encoding a Gr1 receptor from Aedes aegypti.
  • nucleic acid or amino acid sequences are well-known in the art.
  • the neurons of the present disclosure may include a Gr2 receptor.
  • Gr2 receptors are known in the art.
  • the Gr2 receptors of the present disclosure may include a Gr2 receptor selected from, for example, Aedes aegypti, Anopheles gambiae, Culex quinquefasciatus, Bombyx mori, Tribolium castenium, Phlebotomus papatasi, Heliconius melpomene, Manduca sexta , and Mayetiola destructor.
  • a homolog or an ortholog or any known or putative Gr2 receptor may also be used in the methods and systems described herein.
  • a homolog may be a protein whose nucleic acid sequence that encodes that protein has a similar sequence to the nucleic acid sequence that encodes a known or putative Gr2 receptor, or a protein whose amino acid sequence is similar to the amino acid sequence of a known or putative Gr2 receptor.
  • Gr2 homologs may have functional, structural or genomic similarities to any known or putative Gr2 receptor.
  • a homolog and/or ortholog of a Gr2 receptor is a protein whose nucleic acid sequences have at least 30%, 40%, 50% 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the nucleic acid sequence encoding any known or putative Gr2 receptor.
  • a homolog of a Gr2 receptor is a protein whose amino acid sequence has at least 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence encoding any known or putative Gr2 receptor.
  • the Gr2 receptor may be from one or more arthropod species.
  • the Gr2 receptor is a homolog or ortholog of the Gr2 receptor from Aedes aegypti .
  • the Gr2 receptor has at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a polypeptide encoding a Gr2 receptor from Aedes aegypti.
  • the neurons of the present disclosure may include a Gr3 receptor.
  • Gr3 receptors are known in the art.
  • the Gr3 receptors of the present disclosure may include a Gr3 receptor selected from, for example, Aedes aegypti, Anopheles gambiae, Culex quinquefasciatus, Bombyx mori, Tribolium castenium, Phlebotomus papatasi, Heliconius melpomene, Manduca sexta , and Mayetiola destructor.
  • a homolog or an ortholog or any known or putative Gr3 receptor may also be used in the methods and systems described herein.
  • a homolog may be a protein whose nucleic acid sequence that encodes that protein has a similar sequence to the nucleic acid sequence that encodes a known or putative Gr3 receptor, or a protein whose amino acid sequence is similar to the amino acid sequence of a known or putative Gr3 receptor.
  • Gr3 homologs may have functional, structural or genomic similarities to any known or putative Gr3 receptor.
  • a homolog and/or ortholog of a Gr3 receptor is a protein whose nucleic acid sequences have at least 30%, 40%, 50% 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the nucleic acid sequence encoding any known or putative Gr3 receptor.
  • a homolog of a Gr3 receptor is a protein whose amino acid sequence has at least 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence encoding any known or putative Gr3 receptor.
  • the Gr3 receptor may be from one or more arthropod species.
  • the Gr3 receptor is a homolog or ortholog of the Gr3 receptor from Aedes aegypti .
  • the Gr3 receptor has at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a polypeptide encoding a Gr3 receptor from Aedes aegypti.
  • the detection of the skin odor by a Gr1-, Gr2- and/or Gr3-expressing neuron may be measured by any suitable methods and techniques known in the art. Suitable methods and techniques include, for example, measuring electrophysiological parameters.
  • Suitable methods and techniques include, for example, measuring electrophysiological parameters.
  • EAGs electroantennograms
  • EPGs electropalpograms
  • Another method of detecting skin odor activation is using imaging of neural activity using fluorescent or luminescent reporters of calcium, pH, voltage, and synaptic release.
  • the detection of the skin odor by a Gr1-, Gr2- and/or Gr3-expressing neuron after contact with the candidate compound or plurality of candidate compounds is compared with the detection of the skin odor by a Gr1-, Gr2- and/or Gr3-expressing neuron in the absence of the candidate compound or plurality of candidate compounds to determine whether a candidate compound is an arthropod repellent.
  • a candidate compound is selected as an arthropod repellent based on the ability of the candidate compound to mask the detection of the skin odor by a Gr1-, Gr2- and/or Gr3-expressing neuron. In certain embodiments, a candidate compound is selected as an arthropod repellent based on at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% masking of the detection of the skin odor by a Gr1-, Gr2- and/or Gr3-expressing neuron.
  • a candidate compound is selected as an arthropod repellent based on the ability of the candidate compound to inhibit the detection of the skin odor by the Gr1-, Gr2- and/or Gr3-expressing neuron.
  • a candidate compound is selected as an arthropod repellent based on at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% inhibition of the detection of the skin odor by the Gr1-, Gr2- and/or Gr3-expressing neuron.
  • One or more candidate compounds may be identified as an arthropod attractant based on the activation of the Gr1-, Gr2- and/or Gr3-expressing neuron.
  • a candidate compound is selected as an arthropod attractant based on at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% increase in activation of the Gr1-, Gr2- and/or Gr3-expressing neuron over baseline activity in standard room air.
  • the system includes: a) a sample that includes a Gr1-, Gr2- and/or Gr3-expressing neuron; b) a skin odor; and c) one or more compounds that each is a repellent for at least one arthropod species, wherein the one or more compounds each masks or inhibits the detection of the skin odor by the Gr1-, Gr2- and/or Gr3-expressing neuron.
  • the one or more compounds each masks or inhibits at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the detection of the skin odor by the Gr1-, Gr2- and/or Gr3-expressing neuron.
  • the skin odor may be an individual odor or the skin odor may be made up of a plurality of odors.
  • the Gr1-, Gr2- and/or Gr3-expressing neuron may be from an arthropod or, in certain embodiments, an insect.
  • a candidate compound is selected as an arthropod attractant based on at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% activation of the Gr1-, Gr2- and/or Gr3-expressing neuron.
  • the following compounds have been identified using the methods and systems described herein to modulate an arthropod olfactory neuron, such as a Gr1-, Gr2- and/or Gr3-expressing neuron.
  • an arthropod olfactory neuron such as a Gr1-, Gr2- and/or Gr3-expressing neuron.
  • One or more of such compounds may be used in a composition that is an arthropod repellent.
  • the compound has a structure of formula (I):
  • X 1 and X 2 are each independently selected from the group consisting of O, S and NH;
  • R 1 and R 2 are each independently selected from the group consisting of H, D, halide, optionally substituted aliphatic group, and optionally substituted hetero-aliphatic group; or R 1 and R 2 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R 1 and R 2 when X 1 and X 2 are each O, and R 1 or R 2 is methyl, then the other R 2 or R 1 is H, D, halide, optionally substituted C 2+ aliphatic group, and optionally substituted hetero-aliphatic group.
  • R 1 and R 2 when X 1 and X 2 are each O, R 1 and R 2 are each other than methyl (i.e., the compound of formula (I) is other than methyl acetate).
  • aliphatic compounds include any non-aromatic compounds, and may be saturated or unsaturated with one or more double or triple bonds.
  • aliphatic compounds include (C 1 to C 15 )alkyls, (C 1 to C 15 ) alkenyls, (C 1 to C 15 )alkynyls, cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • hetero-aliphatic groups include any aliphatic compounds in which at least one carbon atom is replaced by a heteroatom, such as nitrogen, oxygen or sulfur.
  • hetero-aliphatic groups may include (C 1 to C 14 )hetero-alkyls, (C 1 to C 14 )hetero-alkenyls, and (C 1 to C 14 )hetero-alkynyls.
  • Optionally substituted groups which contain halogens may include, for example, haloalkanes, and haloalkenes.
  • Optionally substituted groups which contain oxygen may include, for example, hydroxyls, carbonyls, aldehydes, haloformyls, carbonate esters, carboxylates, carboxyls, esters, ethers, peroxides, hydroperoxides, hemiacetals, hemiketals, acetals, ketals, orthoesters, and orthocarbonate esters.
  • Optionally substituted groups which contain nitrogen may include, for example, amides, amines, imines, enamines, imides, azides, azo compounds, cyanates, nitrates, nitros, nitriles, nitrosos, and pyridyls.
  • Optionally substituted groups which contain sulfur may include, for example, thiols, sulfides, disulfides, sulfoxides, sulfones, sulfinos, sulfos, thiocyanates, thiones, and thials.
  • Optionally substituted groups which contain phosphorus may include, for example, phosphinos, phosphonos, and phosphates; optionally substituted groups which contain boron, such as boronos, boronates, borinos, and borinates.
  • Optionally substituted groups which contain silicon may include, for example, silyl ethers, silicates, siloxanes, and silanes.
  • the compound has a structure of formula (Ia):
  • R 1 and R 2 are each independently selected from the group consisting H, OH, SH, an optionally substituted aliphatic or hetero-aliphatic group having 1 to 6 carbon atoms, and a cyclic group having 4 to 8 ring carbon atoms; or R 1 and R 2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 3 to 6 ring carbon atoms.
  • the aliphatic or hetero-aliphatic groups may be straight or branched, and saturated or unsaturated.
  • R 1 or R 2 when R 1 or R 2 is methyl, then the other R 2 or R 1 is H, D, halide, optionally substituted C 2+ aliphatic group, and optionally substituted hetero-aliphatic group. In certain embodiments of formula (Ia), when R 1 and R 2 are each other than methyl (i.e., the compound of formula (Ia) is other than methyl acetate).
  • R 1 and R 2 are each independently selected from the group consisting of H, OH, SH, an optionally substituted aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms; or R 1 and R 2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • R 1 is H, OH, SH, an optionally substituted aliphatic or hetero-aliphatic group having 1 to 6 carbon atoms.
  • R 2 is an optionally substituted aliphatic group
  • R 1 is a cyclic group having 4 to 8 ring carbon atoms, then the cyclic group is other than optionally substituted aryl.
  • R 2 is an optionally substituted aliphatic group, and R 2 is a cyclic group having 4 to 8 ring carbon atoms, then the cyclic group is other than aryl substituted with an optionally substituted amino group.
  • the compound has a structure of formula (Ib):
  • R 1 and R 2 are each independently selected from the group comprising H, OH, SH, an optionally substituted aliphatic or hetero-aliphatic group having 1 to 6 carbon atoms, and a cyclic group having 4 to 8 ring carbon atoms; or R 1 and R 2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 3 to 6 ring carbon atoms.
  • R 1 and R 2 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms; or R 1 and R 2 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound of formula (I) is selected from methyl propanoate, methyl 2-methylpropanoate, propyl acetate, ethyl acetate, propyl formate, prop-2-enyl-propanoate, 2-methylpropyl formate, methyl butanoate, methyl acetate, methyl propionate, propyl formate, isobutyl formate, methyl isobutyrate, methyl butyrate, ethyl formate, methyl methacrylate, alpha-angelica lactone, allyl propionate, allyl butyrate, dimethyl carbonate, methyl 2-methylprop-2-enoate, ethyl formate, ethyl(E)-but-2-enoate, prop-2-enyl-butanoate, oxolan-2-ylmethyl acetate, benzyl formate, propan-2-yl benzoate, 2-phenylethyl 3-methylbutanoate, [
  • the compound of formula (I) is selected from 2,2-dimethyl-3-(2-methyl-propenyl)-cyclopropanecarboxylic acid ethyl ester, acetic acid 2,2,6-trimethyl-6-vinyl-tetrahydro-pyran-4-yl ester, isobutyric acid 1-methyl-1-(4-methyl-cyclohex-3-enyl)ethyl ester, acetic acid 2-isopropylidene-4,8-dimethyl-1,2,3,3a,4,5,6,8a-octahydro-azulen-6-yl ester, (4-tert-butyl-phenyl)-acetic acid methyl ester, acetic acid 1-[2-(3,3-dimethyl-oxiranyl)-ethyl]-1-methyl-allyl ester, pentanoic acid 5,5,6-trimethyl-bicyclo[2.2.1]hept-2-yl ester, (1H-indol
  • the compound has a structure of formula (II):
  • X 3 and X 4 are each independently selected from the group consisting O, S and NH;
  • R 3 and R 4 are each independently selected from the group consisting of H, D, a halide, and optionally substituted aliphatic groups, or R 3 and R 4 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound has a structure of formula (IIa):
  • R 3 and R 4 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms; or R 3 and R 4 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound of formula (II) is selected from 3-methylcyclopentane-1,2-dione, 3,4-dimethylcyclopentane-1,2-dione, 2-oxopentanoic acid, and 2-oxopropanal.
  • the compound has a structure of formula (III):
  • R 5 and R 6 are each independently selected from the group consisting of H, D, a halide, and optionally substituted aliphatic group;
  • R 7 is selected from the group consisting of an optionally substituted aliphatic group
  • R 5 and R 6 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; or
  • R 6 and R 7 can be linked together to form an optionally substituted ring selected from the group consisting of cycloalkenyl, aryl, and heterocycle.
  • R 5 -R 7 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms.
  • R 5 and R 6 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • R 6 and R 7 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound of formula (III) is selected from propan-2-yl benzoate, 2-phenylethyl(E)-2-methylbut-2-enoate, 4-ethylbenzaldehyde, (E)-2-methylbut-2-enoic acid, 1-phenylbutan-1-one, (E)-2-methylbut-2-enoic acid, 1-phenylbutan-1-one, 3-methylbut-2-enoic acid, (E)-but-2-enoic acid, 2-methylpropyl-(Z)-but-2-enoate, (E)-pent-2-enal, 3-methylcyclopent-2-en-1-one, methyl 2-methylprop-2-enoate, (2E)-3,7-dimethylocta-2,6-dienoic acid, 1-(1H-pyrrol-2-yl)ethanone, and ethyl(E)-but-2-enoate.
  • the compound of formula (III) is selected from N,N-diethyl-4-methyl-benzamide, N-butyl-3-fluoro-benzamide, N-(3-methyl-butyl)-benzamide, N-(tert-butyl)-4-methylbenzamide, 2-carbamoyl-benzoic acid anion, 3-hydroxymethyl-6-methyl-3a,3b,7a,8-tetrahydro-1H-4-oxa-8a-aza-cyclopenta[a]inden-5-one, mandelonitrile benzoate, 7,8-dihydro-1-biopterin, N-(2-formyl-phenyl)-formamide, indolo[2,1-b]quinazoline-6,12-dione, 4-ethylidene-7-hydroxy-6,7,14-trimethyl-2,9-dioxa-14-aza-bicyclo[9.5.1]heptadec-11-ene-3,8,17-trione, [hydroxy
  • the compound has a structure of formula (IV):
  • X 5 is selected from the group consisting of OH, SH, and NH 2 ;
  • R 8 , R 9 and R 10 are each independently selected from the group consisting of H, D, a halides, an optionally substituted aliphatic group; or R 8 and R 9 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound has a structure of formula (IVa):
  • R 8 and R 9 are each independently selected from the group consisting of H, OH, SH, or an optionally substituted aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms; or R 8 and R 9 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound of formula (IV) is selected from 4-hydroxy-2,3-dimethyl-2H-furan-5-one, 2-hydroxypropanoic acid, and 3-hydroxybutan-2-one.
  • the compound of formula (IV) is selected from 4-ethylidene-7-hydroxy-6,7,14-trimethyl-2,9-dioxa-14-aza-bicyclo[9.5.1]heptadec-11-ene-3,8,17-trione, 2-hydroxy-2-(1-hydroxy-ethyl)-3-methyl-butyric acid 7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-1-ylmethyl ester, and 2-hydroxy-2-(1-methoxy-ethyl)-3-methyl-butyric acid 7-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-1-ylmethyl ester.
  • the compound has a structure of formula (V):
  • X 6 is selected from the group consisting of O, S, and NH;
  • R 11 and R 12 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or R 11 and R 12 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound has a structure of formula (Va):
  • R 11 and R 12 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms; or R 11 and R 12 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound of formula (V) is selected from ethyl 2-oxopropanoate, methyl 2-oxopropanoate, 4-hydroxy-2,3-dimethyl-2H-furan-5-one, and 3-hydroxybutan-2-one, 2-oxobutanoic acid, 2-oxopentanoic acid, ethyl pyruvate, and methyl pyruvate.
  • the compound has a structure of formula (VI):
  • X 7 , X 8 , and X 9 are each independently selected from the group consisting of O, S, and NH;
  • R 13 and R 14 are each independently selected from the group consisting of H, D, a halide, and an optionally substituted aliphatic group; or R 13 and R 14 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound has a structure of formula (VIa):
  • R 13 and R 14 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or hetero-aliphatic residues having 1 to 4 carbon atoms; or R 13 and R 14 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound of formula (VI) is selected from dimethyl carbonate, 1,3-dimethyl-1H-quinazoline-2,4-dione, 1,3,7-trimethyl-3,7-dihydro-purine-2,6-dione, 5,5-diethyl-pyrimidine-2,4,6-trione, 1,3-dinitro-imidazolidin-2-one, (2,5-dioxo-4-imidazolidinyl) urea, 7,9-dihydro-3H-purine-2,6,8-trione, purine-2,6-dione, 1,3-dimethyl-1H-pyrimidine-2,4-dione, 6-methoxy-3H-benzooxazol-2-one, carbamic acid ethyl ester, 3H-benzothiazol-2-one, 14-nitrooxy-tetradec-5-ene, and 1,2-dihydro-[1,2,4]triazol-3-one.
  • the compound has a structure of formula (VII):
  • X 10 is selected from the group consisting of O, S, and NH;
  • R 15 and R 16 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or R 15 and R 16 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound has a structure of formula (VIIa):
  • R 15 and R 16 are each independently selected from the group consisting of H, OH, SH, or an optionally substituted aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms; or R 15 and R 16 can be linked together form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (VIII):
  • X 11 is selected from the group consisting of OH, SH, and NH 2 ;
  • R 17 , R 18 , and R 19 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or R 18 and R 19 and/or R 20 can be linked together to form an optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • the compound has a structure of formula (VIIIa):
  • R 17 , R 18 , and R 19 are each independently selected from the group consisting of H, OH, SH, or an optionally substituted straight or branched, saturated or unsaturated, aliphatic or hetero-aliphatic residues having 1 to 4 carbon atoms; or two of R 17 , R 18 , and R 19 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (IX):
  • X 12 -X 17 are each independently selected from the group consisting of C, N, O, and S;
  • R 20 R 25 are each independently selected from the group consisting of H, D, a halide, and an optionally substituted aliphatic group; or two or more of R 20 -R 25 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
  • R 20′ -R 25′ are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R 20′ -R 25′ can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
  • any one of R 20 -R 25 and/or R 20′ -R 25′ are absent if by forming a covalent bond to the corresponding X group would result in the X group exceeding the maximum valence for that atom.
  • the compound has a structure of formula (IXa):
  • R 20 , R 22 , R 23 , and R 25 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or
  • R 20 and R 25 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and/or
  • R 22 and R 23 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R 20 , R 22 , R 23 , and R 25 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or hetero-aliphatic group having 1 to 4 carbon atoms.
  • R 20 and R 25 can be taken together form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • R 22 and R 23 can be taken together form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (IXb):
  • R 20 and R 22 -R 25 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R 20 and R 22 -R 25 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R 20 and R 22 -R 25 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or heteroaliphatic groups having 1 to 4 carbon atoms.
  • two or more of R 20 and R 22 -R 25 can be linked together to form an optionally substituted aliphatic or heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (IXc):
  • R 20 and R 22 -R 25 are each independently selected from the group consisting of H, D, a halide, and an optionally substituted aliphatic group; or two or more of R 20 and R 22 -R 25 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R 20 and R 22 -R 25 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or heteroaliphatic group having 1 to 4 carbon atoms.
  • two or more of R 20 and R 22 -R 25 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (IXd):
  • R 21 is selected from the group consisting of H, D, a halides, an optionally substituted aliphatic group.
  • the compound has a structure of formula (X):
  • X 18 -X 22 are each independently selected from the group consisting of C, O, N, and S;
  • R 26 -R 30 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R 26 -R 30 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
  • R 26′ -R 30′ are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more R groups from R 26′ -R 30′ can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
  • any one of R 26 -R 30 and/or R 26′ -R 30′ are absent if by forming a covalent bond to the corresponding X group would result in the X group exceeding the maximum valence for that atom.
  • the compound has a structure of formula (Xa):
  • R 27 and R 29 -R 30 are each independently selected from the group consisting of H, D, a halides, or an optionally substituted aliphatic group; or R 29 -R 30 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R 27 and R 29 -R 30 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or heteroaliphatic residues having 1 to 4 carbon atoms.
  • two of R 29 -R 30 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (Xb):
  • R 26 , and R 28 -R 30 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R 26 , and R 28 -R 30 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R 26 and R 28 -R 30 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or heteroaliphatic groups having 1 to 4 carbon atoms.
  • two or more of R 26 and R 28 -R 30 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 carbon atoms.
  • the compound has a structure of formula (Xc):
  • R 26 , and R 28 -R 30 are each independently selected from the group consisting of H, D, a halide, and an optionally substituted aliphatic group; or two or more of R 26 and R 28 -R 30 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R 26 , and R 28 -R 30 are each independently selected from the group consisting of a halide, or an optionally substituted aliphatic group. In other embodiments of formula (Xc), R 26 , and R 28 -R 30 are each other than H.
  • R 26 and R 28 -R 30 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or heteroaliphatic group having 1 to 4 carbon atoms.
  • two or more of R 26 and R 28 -R 30 can be linked together to form an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (XI):
  • X 23 is selected from the group consisting of O, S, NH, and CH 2 ;
  • R 31 -R 34 are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R 31 -R 34 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
  • R 31′ -R 34′ are each independently selected from the group consisting of H, D, a halides, and an optionally substituted aliphatic group; or two or more of R 31′ -R 34′ can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle; and
  • any one of R 31 -R 34 and/or R 31′ -R 34′ are absent if by forming a covalent bond to the corresponding X group would result in the X group exceeding the maximum valence for that atom.
  • the compound has a structure of formula (XIa):
  • R 31 -R 34 are each independently selected the group consisting of H, D, a halides, and an optionally substituted aliphatic group; and/or two or more of R 31 -R 34 can be linked together to form one or more optionally substituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocycle.
  • R 31 -R 34 are each independently selected from the group consisting of H, OH, SH, and an optionally substituted aliphatic or heteroaliphatic group having 1 to 4 carbon atoms.
  • two or more of R 33 -R 36 can be linked together to form an optionally substituted aliphatic or heteroaliphatic, aromatic, heteroaromatic ring system having 4 to 6 ring carbon atoms.
  • the compound has a structure of formula (XII):
  • W is —NR c R d or —CR c R d R e ;
  • a m is an aliphatic group
  • each A n is independently an aliphatic group
  • each R a , R b , R c , R d and R e is independently H or an aliphatic group
  • each R n is independently H or an aliphatic group
  • x is an integer greater than or equal to 1;
  • W is —NR c R d .
  • x is 0 to 8.
  • the compound of formula (XII) is other than hexan-1-amine.
  • a m is an alkyl. In some embodiments, each A n is an alkyl. In certain embodiments, A m is a (C1-C5) alkyl. In certain embodiments, each A n is a (C1-C5) alkyl.
  • x is 1 or 2;
  • W is —NR c R d ;
  • each R a , R b , R c , R d , and R n is H;
  • each A n and A m is independently alkyl.
  • the compound has a structure of formula (XIIA) or (XIIB):
  • n, m and p in independent an integer greater than or equal to 1.
  • n is 1 to 10, or 1 to 8, or 1 to 5. In one embodiment, n is 1, 2, 3, or 4.
  • m is 1 to 10, or 1 to 8, or 1 to 5. In one embodiment, m is 1, 2, 3, or 4.
  • p is 1 to 10, or 1 to 8, or 1 to 5. In one embodiment, p is 1, 2, 3, or 4.
  • the compound is:
  • the compound is:
  • compositions comprising one or more compounds of formula (I)-(XII).
  • the composition includes two or more compounds of formula (Ia), (III) and (Va), or any combination thereof.
  • the composition includes two or more compounds of formula (Xb) and (XIa), or any combination thereof.
  • the compound identified according to the methods and systems described herein are selected from Table A below. Provided are also compositions including one or more, two or more, or three or more compounds selected from Table A below.
  • compositions may further include thickeners, buffering agents, chelating agents, preservatives, fragrances, moisturizers, antioxidants, gelling agents, stabilizers, surfactants, emollients, carriers, coloring agents, aloe vera, waxes, lanolins, other penetration enhancers and mixtures thereof, therapeutically or cosmetically active agents, insecticidals, or any combination thereof.
  • the composition may be formulated for the topical administration of the composition to the skin of a subject (e.g., a human).
  • compositions described herein may be solid-based, liquid-based, gas-based, or a mixture thereof.
  • Liquid-based formulations may be aqueous-based or non-aqueous-based (e.g., organic solvents), or combinations thereof, and may be employed as lotions, ointments, foams, gels, suspensions, emulsions, microemulsions or emulsifiable concentrates or the like.
  • the compositions may also be formulated to be slowly released from a patch or canister.
  • compositions described herein may further include one or more carrier formulation agents, including commercially-available organic and inorganic liquid carriers, solid carriers, or semi-solid carriers or carrier formulations.
  • organic liquid carriers include liquid aliphatic hydrocarbons (e.g., pentane, hexane, heptane, nonane, decane and their analogs) and liquid aromatic hydrocarbons.
  • other liquid hydrocarbons include oils produced by the distillation of coal and the distillation of various types and grades of petrochemical stocks, including kerosene oils that are obtained by fractional distillation of petroleum.
  • Other petroleum oils include those generally referred to as agricultural spray oils (e.g., light and medium spray oils that include middle fractions in the distillation of petroleum and which are only slightly volatile).
  • oils are usually highly refined and may contain only minute amounts of unsaturated compounds.
  • oils moreover, are generally paraffin oils and accordingly can be emulsified with water and an emulsifier, diluted to lower concentrations, and used as sprays.
  • Tall oils obtained from sulfate digestion of wood pulp, like the paraffin oils, can similarly be used.
  • Other organic liquid carriers may include, for example, liquid terpene hydrocarbons and terpene alcohols such as alpha-pinene, dipentene, and terpineol.
  • suitable carriers may include, for example, aliphatic and aromatic alcohols, esters, aldehydes, ketones, mineral oil, higher alcohols, finely divided organic and inorganic solid materials.
  • the carrier may include, for example, conventional emulsifying agents, which can be used for facilitating the dispersal of the formulation or composition to the environment, and/or to the surface of a subject or an object.
  • Aliphatic monohydric alcohols may include, for example, methyl, ethyl, normal-propyl, isopropyl, normal-butyl, sec-butyl, and tert-butyl alcohols.
  • Suitable alcohols may include, for example, glycols (e.g., ethylene and propylene glycol) and pinacols.
  • Suitable polyhydroxy alcohols may include, for example, glycerol, arabitol, erythritol, and sorbitol.
  • Suitable cyclic alcohols may include, for example, cyclopentyl and cyclohexyl alcohols.
  • Solid carriers that can be used in the compositions described herein may include, for example, finely divided organic and inorganic solid materials.
  • Suitable finely divided solid inorganic carriers may include, for example, siliceous minerals such as synthetic and natural clay, bentonite, attapulgite, fuller's earth, diatomaceous earth, kaolin, mica, talc, finely divided quartz, as well as synthetically prepared siliceous materials, such as silica aerogels and precipitated and fume silicas.
  • finely divided solid organic materials may include cellulose, sawdust, and synthetic organic polymers.
  • Examples of semi-solid or colloidal carriers may include waxy solids, gels (e.g., petroleum jelly), and lanolin, and mixtures of liquid and solid substances.
  • compositions or formulations described herein may include any conventional “stabilizer” formulation agents known in the art, including, for example, tert-butyl sulfinyl dimethyl dithiocarbonate.
  • compositions described herein may include adjuvant formulation agents used in personal care product formulations, such as thickeners, buffering agents, chelating agents, preservatives, fragrances, antioxidants, gelling agents, stabilizers, surfactants, emollients, coloring agents, aloe vera, waxes, lanolins, other penetration enhancers and mixtures thereof, and therapeutically or cosmetically active agents.
  • adjuvant formulation agents used in personal care product formulations such as thickeners, buffering agents, chelating agents, preservatives, fragrances, antioxidants, gelling agents, stabilizers, surfactants, emollients, coloring agents, aloe vera, waxes, lanolins, other penetration enhancers and mixtures thereof, and therapeutically or cosmetically active agents.
  • Therapeutically or cosmetically active formulation agents useful for the compositions or formulations disclosed herein may include, for example, fungicides, sunscreening agents, sunblocking agents, vitamins, tanning agents, plant extracts, anti-inflammatory agents, anti-oxidants, radical scavenging agents, retinoids, alpha-hydroxy acids, emollients, antiseptics, antibiotics, antibacterial agents, and antihistamines.
  • compositions described herein may further include one or more insect repellent formulation agents known in the art including, for example benzil, benzyl benzoate, 2,3,4,5-bis(butyl-2-ene)tetrahydrofurfural, butoxypolypropylene glycol, N-butylacetanilide, normal-butyl-6,6-dimethyl-5,6-dihydro-1,4-pyrone-2-carboxylate, dibutyl adipate, dibutyl phthalate, di-normal-butyl succinate, N,N-diethyl-meta-toluamide, dimethyl carbate, dimethyl phthalate, 2-ethyl-2-butyl-1,3-propanediol, 2-ethyl-1,3-hexanediol, di-normal-propyl isocinchomeronate, 2-phenylcyclohexanol, p-methane-3,8-diol
  • compositions described herein may include other known compatible active formulation agents including, for example, insecticides, acaricides, rodenticides, fungicides, bactericides, nematocides, herbicides, fertilizers, and growth-regulating agents.
  • the agents may be in the form of particular dosage preparations for specific application made therefrom, such as solutions, emulsions, suspensions, powders, pastes, and granules as described herein or as otherwise known in the art which are thus ready for use.
  • compositions described herein may be administered in combination with other insect control agents.
  • the compositions may employ various chemicals that affect insect behavior, such as insecticides, attractants and/or repellents, or as otherwise known in the art.
  • the compounds identified by the methods and systems herein may also be administered with chemosterilants.
  • the amount of the compounds in the compositions described herein may vary depending on the application.
  • the compositions described herein has at least about 0.0001% by weight of one or more of the compounds identified by the methods or systems described herein, or about 0.0001% to about 99% by weight of one or more of the compounds identified by the methods or systems described herein, or about 0.001% to about 90% by weight of one or more of the compounds identified by the methods or systems described herein, or about 0.01% to about 80% by weight of one or more of the compounds identified by the methods or systems described herein, or about 0.1% to about 70% by weight by weight of one or more of the compounds identified by the methods or systems described herein, or about 1% to about 50% by weight of one or more of the compounds identified by the methods or systems described herein.
  • compositions described herein contain sufficient amounts of the one or more of the compounds identified by the methods or systems described herein so as to modulate arthropod olfactory receptors and influence or control an arthropod's (e.g., insect's) behavior.
  • arthropod's e.g., insect's
  • the one or more of the compounds identified by the methods or systems described herein are incorporated in effective amounts into a composition suitable for applying to the surface of an object or subject, such as to a subject's (e.g., a human's) skin.
  • a composition suitable for topical applications include a vehicle, such as an alcohol based solvent, a lotion such as numerous skin creams known in the art, a silicaceous clay, or a combination thereof.
  • a vehicle such as an alcohol based solvent
  • a lotion such as numerous skin creams known in the art
  • a silicaceous clay or a combination thereof.
  • compositions described herein have a surface evaporation rate of at least a minimum effective evaporation rate.
  • the composition has a surface evaporation rate of at least a minimum effective evaporation rate for at least 1, 2, 3, 4, 5, 6, 7, 8, 10, or 12 hours.
  • the compounds described herein when formulating the compounds described herein for specific topical applications to a subject's (e.g., a human's) skin, the compounds described herein are generally mixed in a dermatologically acceptable carrier, such pharmaceutically acceptable creams, polymers, lotions, gels, and/or liquids.
  • a dermatologically acceptable carrier such pharmaceutically acceptable creams, polymers, lotions, gels, and/or liquids.
  • the pharmaceutically acceptable carriers may further provide water repellency, prevent skin irritation, and/or soothe and condition skin.
  • Factors to consider when selecting a carrier(s) for any formulation with one or more compounds of the disclosure include solubility, commercial availability, cost, evaporation rate, olfactory, stability, and whether the carrier itself exerts a biological effect on arthropod olfactory receptors.
  • the application of the compositions and compounds of the disclosure do not only include human subjects, but include canines, equines, bovines and other animals subject to exoparasitic sanguinivorous
  • the compounds identified by the methods and systems described herein and compositions thereof are effective at affecting arthropod olfactory receptor activity and thus arthropod behavior, under typical conditions of use, it may under some circumstances be desirable to reduce the rate of evaporation thereof.
  • a variety of strategies may be employed to reduce the evaporation rate of the compounds disclosed herein, if so desired. For example, one method is to combine the compounds disclosed herein with a polymer or other inert ingredient, forcing the compounds disclosed herein to migrate through the mixture to the surface before it can evaporate.
  • the compounds described herein may be micro-encapsulated to control rates of evaporation from the surface of a subject or object.
  • a precursor molecule may be prepared, which slowly disintegrates on the surface of the subject or object thereby slowing the evaporation rate of one or more arthropod olfactory receptor modulating compounds disclosed herein to the environment.
  • release of one or more arthropod olfactory receptor modulating compounds of the disclosure may be, for example, by sub-micron encapsulation, in which one or more compounds disclosed herein is encapsulated (surrounded) within a skin nourishing protein or a liposome.
  • the protein or liposome may be used at, for example, a defined concentration.
  • Examples of one or more encapsulated compounds disclosed herein may include water-based lotions, oil-based lotions, gels, or water for spray application.
  • the protein or liposomes After coming in contact with a subject's (e.g., human's) skin the protein or liposomes would begin to breakdown, thereby releasing the encapsulated arthropod olfactory receptor modulating compounds.
  • the process would continue as each microscopic capsule is depleted then replaced in succession by a new capsule that contacts the skin and releases its encapsulated arthropod olfactory receptor modulating compound.
  • the process may take up to 24 hours for one application. Because a protein's and liposome's adherence to the skin is so effective, these formulas are very resistant to perspiration (sweat-off), and water.
  • one or more arthropod olfactory receptor modulating compounds disclosed herein may be encapsulated in polymers.
  • Suitable polymers include, for example, high density polyethylene, low density polyethylene, biodegradable thermoplastic polyurethanes, biodegradable ethylene polymers, and poly(epsilon caprolactone) homopolymers and compositions containing the same, as disclosed for example in U.S. Pat. No. 4,496,467, U.S. Pat. No. 4,469,613 and U.S. Pat. No. 4,548,764.
  • Specific examples of biodegradable polymers include DuPont Biomax® biodegradable polyester and poly-L-lactide.
  • the compounds identified by the methods and systems described herein and compositions thereof may also be applied to or impregnated onto the surfaces of an object.
  • Examples of such applications include applying or impregnating the compounds to clothing, netting, fabrics, bedding, screens, camping gear, leather, felt, and a sheet-like objects such as paper.
  • the compounds of the may be applied or impregnated onto resin collars.
  • the compounds identified by the methods and systems described herein may also be formulated to generate solutions, suspensions, creams, ointments, gels, films or sprays, depending on the desired method of use.
  • the formulation agents may be aerosol-based carriers adapted to disperse the arthropod olfactory receptor modulating compounds of the disclosure into the atmosphere by means of propellants.
  • propellants include, for example, liquefied petroleum gas (hereinafter referred to as “LPG”) and dimethyl ether (hereinafter referred to as “DME”).
  • the compounds identified by the methods and systems described herein may be used in products suitable for human use, including, for example, colognes, lotions, sprays, creams, gels, ointments, bath and shower gels, foam products (e.g., shaving foams), makeup, deodorants, shampoo, hair lacquers/hair rinses, and personal soap compositions (e.g., hand soaps and bath/shower soaps).
  • products suitable for human use including, for example, colognes, lotions, sprays, creams, gels, ointments, bath and shower gels, foam products (e.g., shaving foams), makeup, deodorants, shampoo, hair lacquers/hair rinses, and personal soap compositions (e.g., hand soaps and bath/shower soaps).
  • the compounds identified by the methods and systems described herein may be emitted from vaporizers, treated mats, cylinders, oils, candles, wicked apparatus, and fans.
  • the compounds may be used to form vapors in barns, houses, or patios to repel insect pest and/or mask a subject from an arthropod pest.
  • Certain compounds identified herein may antagonize, agonize, and/or superagonize arthropod olfactory and/or taste receptors so as to control or influence arthropod behavior, and/or to mask the olfactory cues of a subject or an object.
  • Other compounds identified herein as an arthropod repellent may be used as arthropod repellents or attractants, as masking agents for a subject or an object olfactory cues; and/or to control and influence insect behavior, such as triggering avoidance behavior, feeding behavior, mate seeking behavior, and/or indifference to olfactory cues from a subject or an object.
  • the compounds and compositions described herein may be used for inhibiting, preventing or reducing the incidence of arthropod-borne disease in a subject, by superagonizing and/or antagonizing one or more olfactory receptors of an arthropod.
  • the receptor activity is modulated so that the arthropod has limited to no attraction to the olfactory cues emanating from a subject, thereby inhibiting, preventing or reducing the incidence of arthropod-borne disease in a subject.
  • the arthropod-borne disease is selected from malaria, dengue, yellow fever, river blindness, lymphatic filariasis, sleeping sickness, leishmaniasis, epidemic polyarthritis, West Nile virus disease Lyme disease, Rocky Mountain Fever, and Australian encephalitis, or any combination thereof.
  • one or more of the compounds of formulae (Ia), (Va), (III), and (XII), as described above, or any combinations thereof can be used as arthropod repellents.
  • two or more of the compounds of formulae (Ia), (Va), and (III), or any combination thereof, are arthropod repellents.
  • compositions including two or more compounds selected from compounds of formulae (IA), (VA), and (III), or any combination thereof, for use as an arthropod repellent.
  • the repellent composition includes:
  • the repellent composition includes:
  • the repellent composition includes:
  • one or more of the compounds of formula (XII) are arthropod repellents.
  • compositions including one or more compounds of formula (XII) for use as an arthropod repellent are also compositions including one or more compounds of formula (XII) for use as an arthropod repellent.
  • any combinations of the repellents disclosed herein may be used together in a blend.
  • a blend of compounds selected from compounds of formulae (Ia), (Va), (III), and (XII), or any combination thereof may be used.
  • the blend may include a compound from each formula, or multiple compounds for a formula, or any combination thereof (e.g., a compound from one formula and multiple compounds from another formula).
  • the blend may include two compounds of formula (Ia) and a compound of formula (XII).
  • the blend may include one compound of formula (Ia), one compound of formula (Va), and one compound of formula (XII).
  • the repellent blend may include two or more compounds, three or more compounds, or four or more compounds. In one embodiment, the repellent blend may include, two, three or four compounds of formulae (Ia), (Va), (III), and (XII), or any combination thereof.
  • the repellent compositions includes a combination of pyruvate inhibitors and superactivators.
  • the repellent composition includes: i) one or more pyruvate inhibitors selected from the compounds of Table A, Group II; and ii) one or more superactivators selected from the compound of Table A, Group III.
  • the repellent composition includes propanal, thiophene-2-thiol, or a combination thereof.
  • the arthropod repellents identified according to the methods or systems described herein may be formulated into a repellent for topical application, such as in the form of a lotion, cream, spray or dust.
  • the repellent may be included in, for example, a vaporizer, a treated mat, treated outerwear, an oil, a candle, or a wicked apparatus.
  • one or more of the compounds of formulae (Ia), (Xb), (Xc), and (XIa), as described above, or any combination thereof, can be used as arthropod attractants.
  • compositions including one or more of the compounds of formulae (Ia), (Xb), (Xc), and (XIa), or any combination thereof, for use as a arthropod attractant.
  • the attractant composition includes two or more compounds of formula (Ia), (Xb) and (XIa), or any combination thereof.
  • the attractant composition includes two or more compounds of formula (Xb) and (XIa), or any combination thereof.
  • the attractant composition includes:
  • the attractant composition includes a cycloalkanone, and optionally one or more compounds selected from compounds of formulae (Ia), (Xb), (Xc), and (XIa), or any combination thereof.
  • the cycloalkanone is a C 4 to C 6 cycloalkanone.
  • the cycloalkanone is cyclopentanone.
  • the attractant composition includes cyclopentanone and ethyl acetate.
  • the attractant compositions includes two or more, three or more, or four or more compounds selected from Table A, Group I. In certain embodiments, the composition includes two, three, or four compounds selected from Table A, Group I.
  • the attractant composition includes one or more, two or more, three or more, or four or more compounds selected from 2-methylpropan-1-ol, 2-methyloxolane, 3-methylbut-3-en-1-ol, butan-2-ol, propan-2-yl formate, propan-1-ol, methyl formate, cyclopentanol, and cyclopentane.
  • the attractant composition includes one or more, two or more, three or more, or four or more compounds selected from 2-methyloxolane, propan-2-yl formate, methyl formate, cyclopentanol, and cyclopentane.
  • the arthropod attractants identified according to the methods or systems described herein may be used to lure an arthropod into a trap.
  • the trap may be suction-based, light-based, electric current-based.
  • CpA-off and sham treated mosquitoes were pre-treated for 3 min in an upended 1 L glass dish in which 100 ⁇ l of fresh butyryl chloride (1%) or paraffin oil was allowed to vaporize for 10-20 min.
  • the odor delivery system for different screens is shown in FIG. 7 b ; solvent responses during the same recording session were subtracted. Inhibition screen was tested.
  • the 3-s stimulus was delivered from a 10 ml disposable pipette using a CS-55 stimulus controller (Syntech), CO 2 was delivered, and responses to subsequent odor stimuli were calculated by subtracting baseline activity 1 s prior to each stimulus.
  • a panel of odorants selected from the hundreds of compounds that were detected in human skin, sweat, or associated microbial odors for structural similarity to known ligands of cpA (Table 1 below).
  • the panel of odorants were tested for activity with single-sensillum electrophysiology. Over 35% of these odorants activated the neuron strongly (>30 spikes s ⁇ 1 ) in A. aegypti ( FIG. 1 c ). The neuron's responses to these skin-derived odorants were observed to be comparable to its response to CO 2 ( FIG. 1 d , FIG. 9 a ) and are dose-dependent ( FIG. 1 e ).
  • This Example demonstrates the involvement of cpA activation by human odor for attraction, using a novel chemical-based strategy to shut down the activity of the CO 2 receptor in A. aegypti.
  • Butyryl chloride is a reactive volatile compound and is structurally related to two of the strongest known inhibitors of the CO 2 receptor, butyraldehyde and butanoic acid ( FIG. 2 a ).
  • a single puff of 1% butyryl chloride inhibits cpA from firing in response to subsequent CO 2 stimuli.
  • a 3-min exposure to a small quantity (100 1, 10 ⁇ 2 ) of butyryl chloride volatiles in an upended glass dish was determined to completely abolished cpA's subsequent responses to 1% CO 2 ( FIGS. 2 b and 2 c ) or exhaled breath (not shown) when tested in a period ⁇ 5-20 min after exposure.
  • the neuron's responses to activating skin odorants were also substantially reduced after this pre-exposure (FIGS. 2 b and 2 c ).
  • the inhibition of cpA was observed to be long-lasting and recovered to control levels between 12-24 hours after treatment ( FIG. 9 b ).
  • ligands that have stronger effects on cpA activity are identified using an in silico screen. Such ligands are pleasant smelling, safe, and affordable.
  • structural features shared amongst known ligands (inhibitors and activators) of the CO 2 -sensitive neuron were identified and a structure comparison approach was used to identify new ligands from an extremely large chemical space (>440,000, including 3,197 volatiles from natural sources) ( FIG. 3 a ).
  • a single energy-minimized 3D structure was obtained for each odor in the training set and the values for 3,224 molecular descriptors from Dragon (Talete) were calculated.
  • a small subset of molecular descriptors whose values were highly correlated with electrophysiological activity was selected through application of a Sequential Forward Selection method. This process was applied independently for each of the training sets, resulting in three separate activity-optimized molecular descriptor sets (Tables 2a, 2b and 2c below). 3D and 2D molecular descriptors were preferentially selected, suggesting that shape-related features were important for interaction with the receptor.
  • edge adjacency 2 1 matrix weighted by dipole indices moments piPC04 molecular multiple path count of walk and path 2 1 order 04 counts MATS4e Moran autocorrelation - lag 4/ 2D 2 1 weighted by atomic Sanderson autocorrelations electronegativities ESpm14d Spectral moment 14 from edge edge adjacency 2 1 adj. matrix weighted by dipole indices moments Mor12m 3D-MoRSE - signal 12/weighted 3D-MoRSE 3 1 by atomic masses descriptors
  • edge adjacency 2 1 matrix weighted by resonance indices integrals Mor16m 3D-MoRSE - signal 16/weighted 3D-MoRSE 3 3 by atomic masses descriptors X5A average connectvity index chi-5 connectivity 2 1 indices EEig02r Eigenvalue 02 from edge adj.
  • edge adjacency 2 2 matrix weighted by resonance indices integrals RDF055m Radial Distribution Function - 5.5/ RDF descriptors 3 1 weighted by atomic masses EEig04d Eigenvalue 04 from edge adj.
  • the library of >440,000 chemicals by their computationally determined similarity to known ligands using the three optimized descriptor sets and generated three lists of predicted ligands that cumulatively represent numerous potential ligands for the CO 2 receptor-expressing cpA neuron.
  • a cpA Inhibitor Reduces Attraction of Mosquitoes to Skin
  • This Example demonstrates that an inhibitory odorant may block attraction of mosquitoes to skin.
  • aegypti Forty 4-10-day-old female A. aegypti were starved 24 hrs and released in a 30 ⁇ 30 cm cage with a glass top, and trials commenced between 1400 and 1700 hrs.
  • the cpA inhibitor ethyl pyruvate was selected for testing since it is listed as a GRAS compound, is approved as a flavor agent in food, and has a pleasant smell (fruity, sweet, rum, caramel) (Table 3 above). Ethyl pyruvate completely eliminates response of the cpA neuron to human foot odor when they are presented together ( FIG. 4 b ).
  • An arm-in-cage repellency assay was used in this Example using gloves with chemical treated mesh-covered windows to quantify attraction of A. aegypti mosquitoes to the human hand without exposing the hand to mosquito bites or skin to contact with test chemicals. Ethyl pyruvate substantially reduced the number of times mosquitoes landed on the mesh over a human hand ( FIG. 4 c ).
  • the simplest interpretation of these results when considered along with the previous wind tunnel experiments is that inhibition of the cpA neuron reduces attraction by masking detection of skin odor.
  • This Example demonstrates whether an odorant that can mimic CO 2 -mediated activation of the cpA neuron can substitute for CO 2 as an effective lure.
  • Cyclopentanone is a strong activator in both these species, is approved as a flavor and fragrance agent, is listed as a GRAS substance, and also has a pleasant minty smell (Table 3 above). Cyclopentanone mimics CO 2 's temporal activation profile to repeated 1-s stimuli ( FIG. 4 e,f ), and the cpA neuron tracks changes in levels of both compounds with similar temporal acuity ( FIG. 4 e , FIG.
  • cyclopentanone as a lure was tested using traps in controlled semi-field experiments with C. quinquefasciatus , a mosquito present in Southern California, where the experiments took place. 50 female mosquitoes were released overnight in a modified greenhouse that contained two counter-flow geometry mosquito traps ( FIG. 4 g ). One trap was baited with an evaporative lure of cyclopentanone diluted in water, and the second trap was baited with water alone. Mosquitoes preferred cyclopentanone over solvent-baited traps in a dose-dependent manner ( FIGS. 4 h and 4 i ).
  • This Example explores the nature of the odorant chemical space detected by the cpA neuron.
  • a single energy-minimized 3D structure was generated for each chemical using Omega2 software (OpenEye). 3,224 molecular descriptors were calculated from 3D structures with the Dragon software package (Talete), values were normalized across compounds, and descriptors that did not show variation were removed. Optimized descriptor subsets were iteratively identified using a Sequential Forward Selection (SFS) method. The SFS approach selected descriptors that increased the correlation between ligand activity and chemical similarity, calculated using Euclidean distance from descriptor values. Ligands that evoked >30 spikes s ⁇ 1 were classified as activators, and those that reduced baseline firing rate by >5 spikes s ⁇ 1 were classified as inhibitors.
  • SFS Sequential Forward Selection
  • Each activity-optimized descriptor set was applied to rank a library of >440,000 compounds based on the Euclidean distance of each chemical from a previously known ligand.
  • the compound library comprised 3,197 volatile compounds from known origins including plants 51 , insects 52 , humans 20-23,53-55 , fragrance collection 56 including fruit and floral volatiles, and additional compounds from the eMolecules catalogue selected for having similar physical properties to known odorants ( ⁇ 350 MW and atoms C, O, N, H, I, Cl, S, F).
  • a new receptor-optimized descriptor set (Table 4) was calculated based on ligand activity data for A. aegypti alone (this study). This descriptor set was utilized to train a Support Vector Machine (SVM) using regression and a radial basis function kernel available in the R package e1071, which integrates libsvm. Optimal gamma and cost values were determined using the Tune.SVM function. The resulting trained SVM was then applied to predict activity for compounds from the >440,000 compounds.
  • SVM Support Vector Machine
  • Predicted ligands were screened for organoleptic odor profile using a flavor and fragrance database. Compounds that did not have foul smells and were categorized as flavor, fragrance or cosmetic agents were considered for purchase. A few additional compounds were also selected after cross-checking MSDSs and other literature to leave out carcinogens, neurotoxins, etc.
  • the action potentials evoked in the cp sensillum by CO 2 , whole foot odor, and odorants from multiple structural classes were first analyzed to confirm that cpA's action potentials can be distinguished unambiguously in each case by their characteristically large relative spike amplitude ( FIG. 8 ).
  • the 3 sets of optimized descriptors used to predict cpA ligands include a total of 64 molecular descriptors representing structural features that predict cpA activity, so were used to map the position of each tested skin odorant in 64-dimensional space.
  • PCA Principle component analysis
  • this Example seeks to determine whether an additional set of 110 compounds that had previously been tested on an A. gambiae odor receptor (Or) repertoire, including many skin odorants, occupied a similar region of chemical space. Although these diverse compounds are broadly dispersed, they show limited overlap with the cpA ligand space (black dots, FIG. 5 a ). The functional groups were observed to distributed widely in optimized-descriptor defined chemical space ( FIG. 5 b ). By superimposing activity of the cpA ligands using bubble plots as before, it becomes apparent that stronger ligands include chemicals from diverse functional classes ( FIG. 5 c ). Presumably relevant parts of 3D chemical structure are more important in bringing these ligands together in chemical space than characteristics like functional group.
  • Hierarchical clustering was used to group ligands of the CO 2 receptor by structural similarity, measured by Euclidean distance in 64D optimized descriptor space ( FIG. 5 c ).
  • the resulting tree had roughly three branches, each populated by structurally distinct odor classes: substituted pyrazines and pyridines, other cyclic compounds, and short aliphatic chemicals.
  • These three broad ligand classes and CO 2 appear structurally different, and it will be interesting to test whether they bind to different regions of the heteromeric CO 2 receptor (Gr1, Gr2, and Gr3).
  • SVM Support Vector Machine
  • AUC Area-under-curve
  • Dose response values for spermidine and spermine were also determined, as summarized in Table 7 below.
  • the polyamines were diluted 0.001 to 10% in paraffin oil (PO).

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US10768168B2 (en) 2020-09-08
US20170292944A1 (en) 2017-10-12
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US20180188235A1 (en) 2018-07-05

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