The Scripps Research Institute

Evan T Powers

Jeffery W Kelly

Hossein Razavi

Yoshiki Sekijima

Elizabeth K Culyba

Joshua L Price

Jeffrey W Kelly

A chimeric therapeutic polypeptide of a pre-existing therapeutic polypeptide is disclosed, as are a method of enhancing folded stabilization and a pharmaceutical composition of the glycosylated chimer. The pre-existing and chimeric polypeptides have substantially the same length, substantially the same amino acid residue sequence, and exhibit at least one tight turn containing a sequence of four to about seven amino acid residues in which at least two amino acid side chains extend on the same side of the tight turn and are within less than about 7 &#x212b; of each other. The chimeric therapeutic polypeptide has the sequon Aro-(Xxx)n-(Zzz)p-Asn-Yyy-Thr/Ser (SEQ ID NO:001) within that tight turn sequence such that the side chains of the Aro, Asn and Thr/Ser amino acid residues project on the same side of the turn and are within less than about 7 &#x212b; of each other. That sequon is absent from the pre-existing therapeutic polypeptide.

Reliable stabilization of N-linked polypeptide native states with enhanced aromatic sequons located in polypeptide tight turns

Kinetic stabilization of the native state of transthyretin is an effective mechanism for preventing protein misfolding. Because transthyretin misfolding plays an important role in transthyretin amyloid diseases, inhibiting such misfolding can be used as an effective treatment or prophylaxis for such diseases. Treatment methods are disclosed.

Methods for treating transthyretin amyloid diseases

Pharmaceutically acceptable salt of 6-carboxy-2-(3,5 dichlorophenyl)-benzoxazole, and a pharmaceutical composition comprising the salt thereof

Kinetic stabilization of the native state of transthyretin is an effective mechanism for preventing protein misfolding. Because transthyretin misfolding plays an important role in transthyretin amyloid diseases, inhibiting such misfolding can be used as an effective treatment or prophylaxis for such diseases. Treatment methods, screening methods, as well as specific transthyretin stabilizing compounds are disclosed.

Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding

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La Jolla, CA, United States of America

Evan T Powers