| 摘要 |
The invention provides nucleic acid molecules encoding FGF21 mutant polypeptides, FGF21 mutant polypeptides, pharmaceutical compositions comprising FGF21 mutant polypeptides, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions. In some embodiments, the FGF21 mutant polypeptide comprises a substitution at position 98, 171 and/or 180. |
| 主权项 |
1. An isolated polypeptide comprising an amino acid sequence of SEQ ID NO:4 or 8 with one or more substitutions, wherein the sequence is at least 85% identical to the amino acid sequence of SEQ ID NO: 4 or 8 and the one or more substitutions comprise
(a) a substitution of:
(i) the leucine residue at position 98;(ii) the proline residue at position 171; or(iii) the alanine residue at position 180,wherein the substitution at position 98 is L98R, L98C, L98E, L98Q, L98K or L98T; the substitution at position 171 is P171A, P171R, P171N, P171D, P171C, P171E, P171Q, P171G, P171H, P171K, P171S, P171T, P171W or P171Y; and the substitution at position 180 is A180G, A180E, A180P or A180S; and (b) at least one substitution selected from
(i) a cysteine mutation of Table 2;(ii) an engineered disulfide bond of Table 3;(iii) a stability enhancing mutation from Table 4;(iv) a proteolysis-resistant mutation from Table 5;(v) an aggregation mutation from Table 6;(vi) a C-terminal degradation mutation from Table 7;(vii) a glycosylation mutation from Table 8; and(viii) an O-glycosylation-resistant mutation selected form Table 9;wherein the at least one substitution is not at position 98 when the polypeptide comprises L98R, L98C, L98E, L98Q, L98K or L98T;wherein the at least one substitution is not at position 171 when the polypeptide comprises P171A, P171R, P171N, P171D, P171C, P171E, P171Q, P171G, P171H, P171K, P171S, P171T, P171W or P171Y;wherein the at least one substitution is not at position 180 when the polypeptide comprises A180G, A180E, A180P or A180S, and wherein said polypeptide is an FGF receptor agonist. |
