WO 2013/067519 A2 10 May 2013 (10.05.2013) P O P C T

WO 2013/067519 A2 10 May 2013 (10.05.2013) P O P C T

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/067519 A2 10 May 2013 (10.05.2013) P O P C T (51) International Patent Classification: Not classified BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/US2012/063585 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 5 November 20 12 (05 .11.20 12) NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (25) Filing Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (26) Publication Language: English ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/555,645 4 November 20 11 (04. 11.201 1) U S kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant: PURDUE RESEARCH FOUNDATION UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, [US/US]; 1281 Win Hentschel Boulevard, West Lafayette, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, IN 47906-4182 (US). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (72) Inventors: HILL, Catherine, A.; 606 North 5th Street, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Lafayette, IN 47901 (US). WATTS, Val, J.; 35 14 Advent ML, MR, NE, SN, TD, TG). Court, West Lafayette, IN 47906 (US). Published: (74) Agent: BICKLEY, Patrick, M.; Faegre Baker Daniels LLP, 300 North Meridian Street, Suite 2700, Indianapolis, — without international search report and to be republished IN 46204 (US). upon receipt of that report (Rule 48.2(g)) (81) Designated States (unless otherwise indicated, for every — with sequence listingpart of description (Rule 5.2(a)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: INSECT AND TICK G-COUPLED RECEPTORS USEFUL A S TARGETS FOR INSECTICIDES AND COMPOUNDS AND REAGENTS IDENTIFIED USING THE SAME c s- )-Fl nt si¾o!(n= ) Asenapine (n=3) Amp r i e (ti=2) C to rp r a (n=7) < [drug] (M) FIG. 13 © (57) Abstract: An approach to identify and evaluate potential insecticide targets using publicly available genome (DNA) sequence information for arthropod disease vector is provided. The utility of this approach is demonstrated by first determining the molecular o and pharmacological properties of two different dopamine (neurotransmitter) receptors identified in the genome of the yellow fever- and dengue-transmitting mosquito, Aedes aegypti. Next, different chemistries were tested for their ability to interact with one of o these dopamine receptors in a chemical compound screen, and "hit" compounds were identified. Finally, it is shown that some of these chemistries, are selective for the mosquito over the human dopamine receptor and that these chemistries caused significant mortality in mosquito larvae 24 hours after exposure. INSECT AND TICK G-COUPLED RECEPTORS USEFUL AS TARGETS FOR INSECTICIDES AND COMPOUNDS AND REAGENTS IDENTIFIED USING THE SAME PRIORITY CLAIM [0001] This application claims the benefit of United States Provisional Patent Application No. 61/555,645, filed on November 4, 201 1, and incorporated herein by reference in its entirety. STATEMENT OF GOVERNMENTAL RIGHTS [0002] This invention was made with government support under grant contract number 09-CRIS-2-2037/IND01 1474 awarded by the United States Department of Agriculture/National Institute of Food and Agriculture; and grant contract no. prime award W81XWH-10-1-0085, sub-award no. PU201596 awarded by the Department of Defense/Telemedicine and Advanced Technology Research Center. The United States Government has certain rights in the invention. FIELD OF THE INVENTION [0003] Aspects of the invention related to identifying G-coupled receptors in insects such as mosquitoes and the design and use of screens that employ these proteins to identify efficacious insecticides. BACKGROUND [0004] Many neglected tropical infectious diseases affecting humans are transmitted by arthropods such as mosquitoes and ticks. New mode-of-action chemistries are urgently sought to enhance vector management practices in countries where arthropod-borne diseases are endemic, especially where vector populations have acquired widespread resistance to insecticides. SUMMARY [0005] Some aspects of the invention include a method of controlling a population of invertebrates. The method comprises contacting an invertebrate with a compound that includes at least one of the group consisting of asenapine, amperozide, cis-(Z)-flupenthixol, benztropine, methiothepin, loxapine, mianserin, clomipramine, amperozide, butaclamol, clozapine, doxepin, and SCH23390 amitriptyline, chlorpromazine chlorprothixene. In some more particular embodiments, the invertebrate is an insect. In some more particular embodiments, the compound includes at least one of the group consisting of asenapine, amperozide, and cis-(z)-flupenthixol. In some more particular embodiments, the compound includes at least one of the group consisting of benztropine, methiothepin, loxapine, chlorprothixene, mianserin, and clomipramine. In some more particular embodiments, the insect is a mosquito. In some more particular embodiments, the compound includes at least one of the group consisting of asenapine, amperozide, cis-(Z)-flupenthixol, chlorpormazine, amitriptyline, and doxepin. In some more particular embodiments, the insect is a termite. In some more particular embodiments, the compound includes at least one of the group consisting of asenapine, cis-(Z)-flupenthixol, amperozide, amitriptyline, and chlorpromazine. In some more particular embodiments, the insect is a cockroach in some more particular embodiments, the compound includes at least one of the group consisting of amitriptyline, chlorpormazine, cis-(Z)-flupenthixol, asenapine, and amperozide. In some more particular embodiments, the invertebrate is an arthropod. In some more particular embodiments, the invertebrate is a tick. In some more particular embodiments, the compound includes at least one of asenapine, chlorpromazine, and amperozide. [0006] Some aspects of the invention include a method of controlling a population of invertebrates. The method comprises contacting an invertebrate with a compound that includes at least one of the group consisting of amitriptyline hydrochloride, (±)-butaclamol hydrochloride, clozapine, doxepin hydrochloride, cis-(Z)- flupenthixol dihydrochloride, methiothepin maleate, mianserin hydrochloride, niclosamide, piceatannol, and resveratrol. In some more particular embodiments, the invertebrate is any one of an arthropod, an insect, a mosquito, a termite, a cockroach, and a tick. [0007] Some aspects of the invention include a method of controlling a population of invertebrates. The method comprises contacting an invertebrate with a compound that includes at least one of the group of chemical scaffolds consisting of dibenzocycloheptane derivatives, phenothiazine derivatives, thioxanthene derivatives, butyrophenone derivatives, diphenyl amine-containing compounds, quinazoline derivatives, benzodiazoxide derivatives, indole derivatives, piperazinylpyrazolopyrimidines, aryldiaminopryimidine, and hexahydrothienopyridines. In some more particular embodiments, the invertebrate is any one of an arthropod, an insect, a mosquito, a termite, a cockroach, and a tick. [0008] Some aspects of the invention include a method of controlling a population of invertebrates. The method comprises contacting an invertebrate with a compound that includes at least 3 conjugated or non-conjugated rings, wherein said rings are independently selected from the group consisting of aromatic, non-aromatic, heterocyclic and non-heterocyclic rings, and wherein heterocyclic rings may independently includes at least one of the following atoms: C, O, N, or S and wherein each ring may be independently, substituted or unsubstituted with at least one of the following groups or atoms including H, amines, imines, ketones, aldehydes, alcohols, thiols, aromatic rings, alkanes, alkenes, alkynes, halogens and the like. In some more particular embodiments, the invertebrate is any one of an arthropod, an insect, a mosquito, a termite, a cockroach, and a tick. [0009] Some aspects of the invention include a method of controlling a population of insects. The method includes contacting an insect with at least polynucleotide that interferes with the expression of a gene having at least 90 percent homology to SEQ ID. NO. 1 or SEQ ID. NO. 3. In some more particular embodiments, the polynucleotide interferes with the expression of at gene that includes or that hybridizes under stringent conditions to SEQ ID. NO. 1 or SEQ ID. NO. 3. [0010] Some aspects of the invention include a method of screening. The method includes expressing a polynucleotide having at least 90 or 95 percent homology to SEQ ID. NO. 1 or SEQ ID. NO. 3, and contacting cells that express said polynucleotide with at least one exogenous compound, wherein said polynucleotide is not expressed in its native host. In some more particular embodiments, the polynucleotide has at least 90 or 95 percent identity to SEQ ID. NO. 1 or SEQ ID. NO. 3. In some more particular embodiments, the polynucleotide is SEQ ID. NO. 1 or SEQ ID. NO. 3. [0011] Some aspects of the invention include a method of screening. The method includes an isolated polypeptide having at least 90 or 95 percent homology to SEQ ID. NO. 2 or SEQ ID. NO. 4; with at least one exogenous compound and detecting a interaction between said polypeptide and the at least one compound. In some more particular embodiments, the polypeptide has at least 90 or 95 percent identity to SEQ ID. NO. 2 or SEQ ID. NO. 4. In some more particular embodiments, the polypeptide is SEQ ID. NO. 2 or SEQ ID. NO. 4. SEQUENCE LISTING [0012] SEQ ID NO.

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