Provided herein are stabilized α-CT polypeptides comprising an alpha-helical segment, and wherein the polypeptide is of Formula (I-1) or Formula (I-2): Rf—XAAs—XA1—XA2—XA3—XA4—XA5—XA6—XA7—XA8—XA9—XA10—XA11—XA12—XA13—XA14—XAAt—Re (I-1) Rf—XAAs—XC1—XC2—XC3—XC4—XC5—XC6—XC7—XC8—XC9—XC10—XC11—XC12—XC13—X
Provided herein are stabilized α-CT polypeptides comprising an alpha-helical segment, and wherein the polypeptide is of Formula (I-1) or Formula (I-2): Rf—XAAs—XA1—XA2—XA3—XA4—XA5—XA6—XA7—XA8—XA9—XA10—XA11—XA12—XA13—XA14—XAAt—Re (I-1) Rf—XAAs—XC1—XC2—XC3—XC4—XC5—XC6—XC7—XC8—XC9—XC10—XC11—XC12—XC13—XC14—XC15—XC16—XC17—XC18—XC19—XC20—XAAt—Re (I-2) wherein the α-CT polypeptide binds to the insulin receptor, and wherein the α-CT polypeptide includes at least one staple (i.e. two cross-linked amino acids) and/or at least one stitch (i.e. three cross-linked amino acids). Further provided are insulin analogs including the stapled or stitched α-CT polypeptides, pharmaceutical compositions thereof, methods of use, e.g., methods of treating a diabetic condition or complications thereof.
대표청구항▼
1. A polypeptide comprising an alpha-helical segment, wherein the polypeptide binds to the insulin receptor, and wherein the polypeptide is of Formula (I-2): or a pharmaceutically acceptable salt thereof; wherein:n=0 or 1;each instance of independently represents a single bond, a double bond, or a
1. A polypeptide comprising an alpha-helical segment, wherein the polypeptide binds to the insulin receptor, and wherein the polypeptide is of Formula (I-2): or a pharmaceutically acceptable salt thereof; wherein:n=0 or 1;each instance of independently represents a single bond, a double bond, or a triple bond;each of Ra1 and Ra2, are, independently, hydrogen; acyl; optionally substituted C1-6 alkyl; or an amino protecting group;each of R2a and R2b is, independently, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted heteroalkyl; optionally substituted carbocyclyl; optionally substituted heterocyclyl;each of R3a and R3b is, independently, optionally substituted alkylene; unsubstituted heteroalkylene; optionally substituted carbocyclylene; or optionally substituted heterocyclylene; or optionally R2a and R3a are joined to form a ring; or optionally R2b and R3b are joined to form a ring;L1 is independently, a bond; optionally substituted C1-10 alkylene; or C(═O)ORL1—;L2 is independently, a bond; optionally substituted C1-10 alkylene; or —C(═O)ORL2—;each of RL1 and RL2 is independently optionally substituted C1-10 alkylene;each instance of Rc1 is independently hydrogen; optionally substituted aliphatic; optionally substituted heteroaliphatic; optionally substituted aryl; optionally substituted heteroaryl; acyl; optionally substituted hydroxyl; optionally substituted thiol; optionally substituted amino; azido; cyano; isocyano; halogen; or nitro;q1 is 0, 1, or 2;Rf is (i) hydrogen; (ii) unsubstituted aliphatic; (iii) acetyl; (iv) acyl; or (v) aliphatic substituted with halogen, ═O, ═S, ═NN(Rbb)2, ═NNRbbC(═O)Raa, ═NNRbbC(═O)ORaa, ═NNRbbS(═O)2Raa, ═NRbb, ═NORcc, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORaa, —ON(Rbb)2, —SH, —SRaa, —SSRcc, —C(═O)Raa, —CO2H, —CHO, —C(ORcc)2, —CO2Raa, —OC(═O)Raa, —OCO2Raa, —C(═O)N(Rbb)2, —OC(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —OC(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —SO2N(Rbb)2, —SO2Raa, —SO2ORaa, —OSO2Raa, —S(═O)Raa, —OS(═O)Raa, —Si(Raa)3, —OSi(Raa)3, —C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —SC(═S)SRaa, —SC(═O)SRaa, —OC(═O)SRaa, —SC(═O)ORaa, —SC(═O)Raa, —P(═O)2Raa, —OP(═O)2Raa, —P(═O)(Raa)2, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —P(═O)2N(Rbb)2, —OP(═O)2N(Rbb)2, —P(═O)(NRbb)2, —OP(═O)(NRbb)2, —P(Rcc)2, —P(Rcc)3, —OP(Rcc)2, —OP(Rcc)3, —B(Raa)2, —B(ORcc)2, —BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, or 5-14 membered heteroaryl; wherein each instance of Raa is, independently, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, or 5-14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; wherein each instance of Rbb is, independently, hydrogen, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)2N(Rcc)2, —P(═O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, or 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and wherein each instance of Rcc is, independently, hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, or 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring;Re is —ORE; —N(RE)2; or —SRE, wherein each instance of RE is, independently, (i) hydrogen; (ii) unsubstituted-aliphatic; (iii) unsubstituted-heteroaliphatic; (iv) optionally substituted aryl; (v) optionally substituted heteroaryl; or (vi) aliphatic substituted with —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORaa, —ON(Rbb)2, —N(Rbb)2, —N(Rbb)3+X−, —N(ORcc)Rbb, —SH, —SRaa, —SSRcc, —C(═O)Raa, —CHO, —OC(═O)Raa, —OCO2Raa, —OC(═O)N(Rbb)2, —NRbbC(═O)Raa, —NRbbCO2Raa, —NRbbC(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —OC(═NRbb)N(Rbb)2, —NRbbC(═NRbb)N(Rbb)2, —NRbbSO2Raa, —SO2N(Rbb)2, —SO2Raa, —SO2ORaa, —OSO2Raa, —S(═O)Raa, —OS(═O)Raa, —Si(Raa)3, —OSi(Raa)3, —C(═S)N(Rbb)2, —SC(═S)SRaa, —SC(═O)SRaa, —OC(═O)SRaa, —SC(═O)ORaa, —SC(═O)Raa, —P(═O)2Raa, —OP(═O)2Raa, —P(═O)(Raa)2, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —P(═O)2N(Rbb)2, —OP(═O)2N(Rbb)2, —P(═O)(NRbb)2, —OP(═O)(NRbb)2, —NRbbP(═O)(ORcc)2, —NRbbP(═O)(NRbb)2, —P(Rcc)2, —P(Rcc)3, —OP(Rcc)2, —OP(Rcc)3, —B(Raa)2, —B(ORcc)2, —BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, or 5-14 membered heteroaryl; wherein each instance of Raa is, independently, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, or 5-14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; wherein each instance of Rbb is, independently, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)2N(Rcc)2, —P(═O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, or 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and wherein each instance of Rcc is, independently, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, or 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; or (vii) two RE groups taken together form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. 2. The polypeptide of claim 1, wherein each instance of the cross-linked amino acids is independently of Formula (i-d), (ii-d), (i-e), or (ii-e): wherein each of Y1 and Y2 is, independently, CR5 or N;R5 is hydrogen, halogen, —NO2, —OH, —CN, or C1-6 alkyl; andeach of j and j1 is, independently, 0, 1, 2, 3, 4, 5, or 6; andeach of k and k1 is, independently, 0 or an integer from 1 to 10, inclusive. 3. The polypeptide of claim 1, wherein R3a is of Formula (G-1): wherein Y1 is a bond, —CR5R6— or —NR1—;each of R5 and R6 is, independently, hydrogen, halogen, —NO2, —OH, —CN, or C1-6 alkyl;R1 is hydrogen; acyl; optionally substituted C1-6 alkyl; or an amino protecting group; andj is 0 or an integer between 1 and 10, inclusive. 4. The polypeptide of claim 1, wherein L1 is of Formula (G-4) or Formula (G-5): wherein each of g and g1 is, independently, 0 or an integer between 1 and 10, inclusive. 5. The polypeptide of claim 1, wherein R3b is of Formula (G-6): wherein Y2 is a bond, —CR5R6—, or —NR1—;each of R5 and R6 is independently hydrogen, halogen, —NO2, —OH, —CN, or C1-6 alkyl;R1 is hydrogen; acyl; optionally substituted C1-6 alkyl; or an amino protecting group; andk is 0 or an integer between 1 and 10, inclusive. 6. The polypeptide of claim 1, wherein L2 is of Formula (G-9) or Formula (G-10): wherein each of h and h1 is, independently, 0 or an integer between 1 and 10, inclusive. 7. The polypeptide of claim 1, wherein is a single bond or a double bond. 8. An insulin analogue comprising: (i) a polypeptide of claim 1;(ii) an insulin A-chain polypeptide; and(ii) an insulin B-chain polypeptide; wherein the polypeptide is linked to the insulin A chain polypeptide via a linker; and the linker is optionally substituted alkylene-C(═O)—, optionally substituted heteroalkylene-C(═O)—, optionally substituted alkenylene-C(═O)—, optionally substituted heteroalkenylene-C(═O)—, optionally substituted alkynylene-C(═O)—, optionally substituted heteroalkynylene-C(═O)—, optionally substituted cycloalkylene-C(═O)—, optionally substituted heterocycloalkylene-C(═O)—, optionally substituted arylene-C(═O)—, optionally substituted heteroarylene-C(═O)—, optionally substituted aralkylene-C(═O)—, or optionally substituted heteroaralkylene-C(═O)—. 9. A pharmaceutical composition comprising a polypeptide of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 10. A method of treating a diabetic condition or a complication thereof comprising administering to a subject in need thereof an effective amount of a polypeptide of claim 1 or a pharmaceutically acceptable salt thereof. 11. A method of treating a diabetic condition or a complication thereof comprising administering to a subject in need thereof an effective amount of an insulin analogue of claim 8 or a pharmaceutically acceptable salt thereof. 12. A method of lowering blood glucose levels in a subject comprising administering to the subject in need thereof an effective amount of a polypeptide of claim 1 or a pharmaceutically acceptable salt thereof. 13. A method of lowering blood glucose levels in a subject comprising administering to the subject in need thereof an effective amount of an insulin analogue of claim 8 or a pharmaceutically acceptable salt thereof. 14. A method of activating an insulin receptor comprising contacting the insulin receptor with an effective amount of a polypeptide of claim 1 or a pharmaceutically acceptable salt thereof. 15. The polypeptide of claim 1, wherein Rt is hydrogen; unsubstituted aliphatic; acetyl; acyl; or aliphatic substituted with ═O; and Re is —ORE; —N(RE)2; or —SRE, wherein each instance of RE is, independently, hydrogen or unsubstituted aliphatic. 16. The polypeptide of claim 1, wherein n is 1.
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