The C‐terminal binding domain of hirullin P18

Krstenansky, John L.; Owen, Thomas J.; Yates, Mark T.; Mao, Simon J.T.

doi:10.1016/0014-5793(90)81208-6

Cited by 11 publications

(3 citation statements)

References 6 publications

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“…The rates of acylation with amido acids 13 were greatly accelerated, probably because of the intervention of 5,6-dihydro-6ketooxazines 15. This observation suggests a general solution to the problem of acylating efficiently the hindered 13-hydroxyl of baccatin III in the partial synthesis of taxol and analogues. [5][6][7] were most effective at promoting the assembly of microtubules from tubulin. Side-chain configuration at C-2' failed to influence activity in the lactate and phenyllactate series, but the natural R configuration led to substantially better activity when the 3'-amide group was present in the side chain.…”

Section: Discussionmentioning

confidence: 99%

“…One of the pitfalls of the taxol partial synthesis devised by Greene and Gueritte-Voegelein7 was the instability during the lengthy esterification of the acid-labile 2'-ethoxyethyl ether protected side chain carboxylic acid. The protection strategy employed in the preparation of 3-8 avoids this difficulty by pairing acid-stable (trichloroethoxy)methyl ether pro- (7) Greene, A. E.; Denis, J.-N.; Guenard, D.; Gueritte-Voegelein, F.; Mangatal, L.; Potier, P. J. Am.…”

Section: Chemistrymentioning

confidence: 99%

“…Hirullin P18 does not contain a Tyr residue near its Cterminus that could be sulfated as in hirudin although it shares the same functional role in the protein. 7 Hirudin PA contains a sulfated Tyr resiude in its C-terminal functional domain, but its location is shifted by one position relative to hirudin. Structure-activity relationships of the unsulfated hirudin and hirudin PA C-terminal peptide analogues are comparable.8'9 However, a comparison of sulfated and nonsulfated hirudin PA analogues or sulfated hirudin and sulfated hirudin PA analogues has not been reported.…”

Section: Introductionmentioning

confidence: 99%

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Biologically active taxol analogs with deleted A-ring side chain substituents and variable C-2' configurations

Swindell¹,

Krauss²,

Horwitz³

et al. 1991

J. Med. Chem.

180

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Taxol, a potent inhibitor of cell replication, enhances the assembly of tubulin into stable microtubules and promotes the formation of microtubule bundles in cells. In addition to its unique mechanism of action, taxol exhibits unusual promise as an antitumor agent, but its application in cancer chemotherapy is hampered by its limited availability. In order to better define the structure-activity profile of taxol for the design of more accessible drugs and to provide insight into the chemical features of the taxol-microtubule interaction, taxol analogues 3-8, with deleted A-ring side chain substituents and both R and S C-2' configurations, were synthesized from baccatin III through esterification at the hindered 13-hydroxyl. Employing an improved hydroxyl protection strategy, lactate analogues 3 and 4 were prepared with reasonable efficiency owing to their simple side-chain structures, while N-benzoylisoserine analogues 7 and 8 were synthesized through esterification reactions whose rates were enhanced greatly by the participation of the amide functionality. Although less biologically active than taxol, analogues 5-7 were found to promote the polymerization of tubulin and to be cytotoxic; 5 and 6 were considerably more effective than 7, whereas 3, 4, and 8 were least active. Interestingly, tubulin polymerization was sensitive to the C-2' configuration only when the amide substituent was present in the side chain. This observation suggests that the 3'-amide substituent plays an important role in preorganizing the taxol side chain to bind to microtubules.

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Section: Discussionmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Biologically active taxol analogs with deleted A-ring side chain substituents and variable C-2' configurations

Swindell¹,

Krauss²,

Horwitz³

et al. 1991

J. Med. Chem.

180

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From natural to synthetic multisite thrombin inhibitors

et al. 1999

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Hirunorms are true hirudin mimetics. The crystal structure of human α‐thrombin‐hirunorm V complex

Simone¹,

Lombardi²,

Galdiero³

et al. 1998

Protein Science

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A novel class of synthetic, multisite-directed thrombin inhibitors, known as hirunorms, has been described recently. These compounds were designed to mimic the binding mode of hirudin, and they have been proven to be very strong and selective thrombin inhibitors. Here we report the crystal structure of the complex formed by human alpha-thrombin and hirunorm V, a 26-residue polypeptide containing non-natural amino acids, determined at 2.1 A resolution and refined to an R-factor of 0.176. The structure reveals that the inhibitor binding mode is distinctive of a true hirudin mimetic, and it highlights the molecular basis of the high inhibitory potency (Ki is in the picomolar range) and the strong selectivity of hirunorm V. Hirunorm V interacts through the N-terminal tetrapeptide with the thrombin active site in a nonsubstrate mode; at the same time, this inhibitor specifically binds through the C-terminal segment to the fibrinogen recognition exosite. The backbone of the N-terminal tetrapeptide Chg1"-Val2"-2-Nal3"-Thr4" (Chg, cyclohexyl-glycine; 2-Nal, beta-(2-naphthyl)-alanine) forms a short beta-strand parallel to thrombin main-chain residues Ser214-Gly219. The Chg1" side chain fills the S2 subsite, Val2" is located at the entrance of S1, whereas 2-Nal3" side chain occupies the aryl-binding site. Such backbone orientation is very close to that observed for the N-terminal residues of hirudin, and it is similar to that of the synthetic retro-binding peptide BMS-183507, but it is opposite to the proposed binding mode of fibrinogen and of small synthetic substrates. Hirunorm V C-terminal segment binds to the fibrinogen recognition exosite, similarly to what observed for hirudin C-termninal tail and related compounds. The linker polypeptide segment connecting hirunorm V N-and C-terminal regions is not observable in the electron density maps. The crystallographic analysis proves the correctness of the design and it provides a compelling proof on the interaction mechanism for this novel class of high potency multisite-directed synthetic thrombin inhibitors.

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The C‐terminal binding domain of hirullin P18

Cited by 11 publications

References 6 publications

Biologically active taxol analogs with deleted A-ring side chain substituents and variable C-2' configurations

Biologically active taxol analogs with deleted A-ring side chain substituents and variable C-2' configurations

From natural to synthetic multisite thrombin inhibitors

Hirunorms are true hirudin mimetics. The crystal structure of human α‐thrombin‐hirunorm V complex

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