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Design of a linker for trivalent thrombin inhibitors: interaction of the main chain of the linker with thrombin.
Biochemistry. 1993 Apr 06; 32(13):3396-404.B

Abstract

N alpha-Acetyl[D-Phe45,Arg47]hirudin45-65 (P53) is a bivalent thrombin inhibitor (Ki = 5.6 nM) that consists of an active site inhibitor segment, [N alpha-acetyl-(dF)PRP]; a fibrinogen recognition exo site inhibitor segment, hirudin55-65 (DFEEIPEEYLQ-OH); and a linker, hirudin49-54 (QSHNDG), connecting these inhibitor segments (DiMaio et al., 1990). The structure-function relationships of the linker were studied using a combination of various omega-amino acids, which modified the length of the linker as well as the number and the locations of peptide bonds. Linkers with 14-18 atoms (counting only the atoms contributing to the length of the linker) showed a competitive inhibition with Ki = 1.7-3.4 nM. The potency of the inhibitors with 12-13-atom linkers was sensitive to the chemical structure of the linker. The high-potency inhibitors showed a competitive inhibition, while the low-potency inhibitors showed a hyperbolic inhibition. Among them, an inhibitor with a 13-atom linker showed the highest potency (Ki = 0.51 nM, an 11-fold improvement from that of P53 above), indicating that this is an optimal linker length. Since linkers with 6-10 atoms failed to bridge the active site and exo site inhibitor segments, a minimum of 11 atoms was required to bridge them, even though the potency of the inhibitor with an 11-atom linker was weak (Ki = 26 nM). Molecular dynamics simulation of the inhibitors with 13-atom linkers suggested that some linkers serve as a functional domain with the amide bond of the linker interacting with thrombin through hydrogen bonds.(

ABSTRACT

TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

8461303

Citation

Szewczuk, Z, et al. "Design of a Linker for Trivalent Thrombin Inhibitors: Interaction of the Main Chain of the Linker With Thrombin." Biochemistry, vol. 32, no. 13, 1993, pp. 3396-404.
Szewczuk Z, Gibbs BF, Yue SY, et al. Design of a linker for trivalent thrombin inhibitors: interaction of the main chain of the linker with thrombin. Biochemistry. 1993;32(13):3396-404.
Szewczuk, Z., Gibbs, B. F., Yue, S. Y., Purisima, E., Zdanov, A., Cygler, M., & Konishi, Y. (1993). Design of a linker for trivalent thrombin inhibitors: interaction of the main chain of the linker with thrombin. Biochemistry, 32(13), 3396-404.
Szewczuk Z, et al. Design of a Linker for Trivalent Thrombin Inhibitors: Interaction of the Main Chain of the Linker With Thrombin. Biochemistry. 1993 Apr 6;32(13):3396-404. PubMed PMID: 8461303.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design of a linker for trivalent thrombin inhibitors: interaction of the main chain of the linker with thrombin. AU - Szewczuk,Z, AU - Gibbs,B F, AU - Yue,S Y, AU - Purisima,E, AU - Zdanov,A, AU - Cygler,M, AU - Konishi,Y, PY - 1993/4/6/pubmed PY - 1993/4/6/medline PY - 1993/4/6/entrez SP - 3396 EP - 404 JF - Biochemistry JO - Biochemistry VL - 32 IS - 13 N2 - N alpha-Acetyl[D-Phe45,Arg47]hirudin45-65 (P53) is a bivalent thrombin inhibitor (Ki = 5.6 nM) that consists of an active site inhibitor segment, [N alpha-acetyl-(dF)PRP]; a fibrinogen recognition exo site inhibitor segment, hirudin55-65 (DFEEIPEEYLQ-OH); and a linker, hirudin49-54 (QSHNDG), connecting these inhibitor segments (DiMaio et al., 1990). The structure-function relationships of the linker were studied using a combination of various omega-amino acids, which modified the length of the linker as well as the number and the locations of peptide bonds. Linkers with 14-18 atoms (counting only the atoms contributing to the length of the linker) showed a competitive inhibition with Ki = 1.7-3.4 nM. The potency of the inhibitors with 12-13-atom linkers was sensitive to the chemical structure of the linker. The high-potency inhibitors showed a competitive inhibition, while the low-potency inhibitors showed a hyperbolic inhibition. Among them, an inhibitor with a 13-atom linker showed the highest potency (Ki = 0.51 nM, an 11-fold improvement from that of P53 above), indicating that this is an optimal linker length. Since linkers with 6-10 atoms failed to bridge the active site and exo site inhibitor segments, a minimum of 11 atoms was required to bridge them, even though the potency of the inhibitor with an 11-atom linker was weak (Ki = 26 nM). Molecular dynamics simulation of the inhibitors with 13-atom linkers suggested that some linkers serve as a functional domain with the amide bond of the linker interacting with thrombin through hydrogen bonds.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0006-2960 UR - https://www.unboundmedicine.com/medline/citation/8461303/Design_of_a_linker_for_trivalent_thrombin_inhibitors:_interaction_of_the_main_chain_of_the_linker_with_thrombin_ L2 - https://antibodies.cancer.gov/detail/CPTC-PRDX2-2 DB - PRIME DP - Unbound Medicine ER -