1. A method for treating a human papillomavirus (HPV) infection in a subject, the method comprising:
administering to a subject in need thereof a composition comprising a compound of formula (I) in an amount effective to inhibit HPV activity, wherein the compound of formula (I) is:
and wherein R1, R2, R3, R4, R5, R6 and R7 are each, independently, selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy, halo, hydroxy, carboxy, carboxylate, formyl, acyl, cyano, nitro, amino, alkyl amino, SO3H, sulfate, phosphate, methylenedioxy, ethylenedioxy, oxo, thioxo, imino, S(O)nalkyl, S(O)n aryl, S(O)n heteroaryl, S(O)n heterocyclyl, amine, ester, amide, and sulfonamide;
Ar is selected from the group consisting of aryl and heteroaryl;
R8 is selected from the group consisting of hydrogen and C1-C10 alkyl; and
X is selected from the group consisting of S and O.
2. The method of claim 1, wherein R1, R2, R3, R4, R5, R6 and R7 is each a hydrogen bond donor moiety.
3. The method of claim 1, wherein R1 is a hydrogen bond donor moiety; R2, R3, R4, R5, R6 and R7 are each hydrogen; X is O; Ar is aryl; and R8 is selected from the group consisting of a C1-C10 alkyl.
4. The method of claim 1, wherein the compound is:
5. The method of claim 1, wherein the subject has a condition selected from the group consisting of common warts, anal warts, oral warts, pharyngeal warts, laryngeal warts, genital warts, an HPV-induced dysplasia, an HPV-induced cancer, and epidermodysplasia verruciformis.
6. The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier or adjuvant.
7. The method of claim 1, wherein the composition is administered orally, parenterally, topically, or by inhalation.
8. A method of identifying a compound that inhibits the activity of the HPV 16 E6 protein, the method comprising:
(a) providing a compound of formula (I):
wherein R1, R2, R3, R4, R5, R6 and R7 are each, independently, selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy, halo, hydroxy, carboxy, carboxylate, formyl, acyl, cyano, nitro, amino, alkyl amino, SO3H, sulfate, phosphate, methylenedioxy, ethylenedioxy, oxo, thioxo, imino, S(O)nalkyl, S(O)n aryl, S(O)n heteroaryl, S(O)n heterocyclyl, amine, ester, amide, and sulfonamide;
Ar is selected from the group consisting of aryl and heteroaryl;
R8 is selected from the group consisting of hydrogen and C1-C10 alkyl; and
X is selected from the group consisting of S and O; and
(b) determining whether the compound blocks the interaction of E6 and a protein containing an E6 binding motif, wherein the compound is identified as inhibiting the activity of the HPV 16 E6 protein if the compound blocks the interaction of E6 and the protein containing an E6 binding motif, compared to a control.
9. The method of claim 8, wherein the protein containing an E6 binding motif is E6BP protein or E6AP protein.
10. The method of claim 9, wherein determining whether the compound blocks the interaction of E6 and the E6BP protein or the E6AP protein comprises analyzing the binding of E6 and E6BP or E6AP in vitro, (i) in the presence of the compound, and (ii) in the presence of the control.
11. The method of claim 8, wherein determining whether the compound blocks the interaction of E6 and the protein containing an E6 binding motif comprises analyzing p53 degradation in vitro, and wherein a compound that inhibits p53 degradation to a greater level than a control is identified as a compound that inhibits the activity of the HPV 16 E6 protein.
12. The method of claim 11, wherein a compound that has an IC50 for inhibition of p53 degradation between 1 and 2 \u03bcM is identified as a compound that inhibits the activity of the HPV 16 E6 protein.
13. A method of identifying a chemical derivative that inhibits the activity of the HPV 16 E6 protein, the method comprising:
(a) providing a compound, wherein the compound is:
(b) generating a chemical derivative of the compound; and
(c) determining whether the chemical derivative blocks the interaction of E6 and a protein containing an E6 binding motif, wherein the chemical derivative is identified as inhibiting the activity of the HPV 16 E6 protein if the chemical derivative blocks the interaction of E6 and the protein containing an E6 binding motif, compared to a control.
14. The method of claim 13, wherein determining whether the chemical derivative blocks the interaction of E6 and the protein containing an E6 binding motif comprises analyzing the binding of E6 and E6BP in vitro.
15. The method of claim 13, wherein determining whether the chemical derivative blocks the interaction of E6 and the protein containing an E6 binding motif comprises analyzing p53 degradation.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A combustor for a gas turbine engine, comprising:
a combustion chamber wall having formed therein at least one hole for admitting air into the combustion chamber;
at least one air intake chute aligned with said hole;
during operation a hoop stress field having regions of high and low stress concentration around said hole;
wherein said chute is provided with a flange disposed around one end thereof, and at least one tab that projects from the outer edge of said flange and is welded to the combustor wall in a region of low stress concentration along the outer edge of the at least one tab such that the at least one tab provides a guide for the location and length of the weld.
2. A combustor as claimed in claim 1 wherein the chute is attached to the combustor wall in at least two regions of low stress concentration.
3. A combustor as claimed in claim 2 wherein areas where the chute is attached to the combustor wall are substantially in the same radial plane.
4. A combustor as claimed in claim 2 wherein the areas of attachment are provided on diametrically opposite sides of said chute.
5. A combustor as claimed in claim 1 wherein the flange is circular.
6. A combustor as claimed in claim 1 wherein the at least one tab projects from the edge of the flange up to about 0.14\xd7 (flange diameter).
7. A combustor as claimed in claim 1 wherein the at least one tab has a length of up to about 0.25\xd7 (flange diameter) of the diameter of the flange.