Immunosuppresive boronic acid dipeptides: correlation between conformation and activity

Kelly, Terence A.; Adams, Julian; Bachovchin, William W.; Barton, Randall W.; Campbell, Scot; Coutts, Simon J.; Kennedy, Charles A.; Snow, Roger J.

doi:10.1021/ja00079a074

Cited by 44 publications

(49 citation statements)

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“…More detailed biological studies, kinetic analysis for inactivation rate constant k inact , and investigations of inhibition mechanism are in progress at present. The results of this study reveal that a series of known inhibitors of DPP IV such as dipeptide boronic acids (43)(44)(45), dipeptide phosphonates (46,47), peptidyl nitriles (49-51), and others can be modified by replacing the amide bonds by fluoroolefin moieties. Because of the anticipated high affinity and stability, the fluoroolefin containing dipeptide peptiomimetics should prove to be very promising inhibitors of ‫ء‬Percentage inhibition was measured after 2-or 30-min incubation in 45 mM phosphate buffer, pH 7.6, at 30°C.…”

Section: Inhibition Of Dpp IVmentioning

confidence: 99%

“…The boronic acids Ala-boroPro, Pro-boroPro, and Val-boroPro are potent and specific reversible inhibitors of DPP IV with K i values in the nanomolar range. However, these compounds lose their inhibitory activity in aqueous solution at neutral pH because of the formation of cyclic species in which the N-terminal amine nitrogen coordinates to the boron atom (37,(43)(44)(45). Peptidyl (␣-aminoalkyl) phosphonate esters (46) and diphenyl phosphonate esters (47) are moderate and specific DPP IV inhibitors.…”

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confidence: 99%

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Inhibition of dipeptidyl peptidase IV by fluoroolefin-containingN-peptidyl-O-hydroxylamine peptidomimetics

Lin

Toscano

Welch

1998

Proc. Natl. Acad. Sci. U.S.A.

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Dipeptidyl peptidase IV (EC 3.4.14.5; DPP IV), also known as the leukocyte differentiation antigen CD26 when found as an extracellular membrane-bound proline specific serine protease, cleaves a dipeptide from the N terminus of a polypeptide chain containing a proline residue in the penultimate position. Here we report that known (Z)-Ala-[CF‫؍‬C]-Pro dipeptide isosteres 1 and 2, which contain O-acylhydroxylamines, were isolated as diastereomeric pairs u-1, l-1, and l-2. The effect of each diastereomeric pair as an inhibitor of human placental dipeptidyl peptidase DPP IV has been examined. The inhibition of DPP IV by these compounds is rapid and efficient. The diastereomeric pair u-1 exhibits very potent inhibitory activity with a K i of 188 nM. Fluoroolefin containing N-peptidyl-O-hydroxylamine peptidomimetics, by virtue of their inhibitory potency and stability, are superior to N-peptidyl-O-hydroxylamine inhibitors derived from an Ala-Pro dipeptide.

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Section: Inhibition Of Dpp IVmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of dipeptidyl peptidase IV by fluoroolefin-containingN-peptidyl-O-hydroxylamine peptidomimetics

Lin

Toscano

Welch

1998

Proc. Natl. Acad. Sci. U.S.A.

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“…Unfortunately, they have a short half-life at neutral pH, caused by cyclisation of the terminal aminofunction with the boronic acid, forming a cyclic, inactive species containing a B-N bond (Fig. 5b) [121][122][123]. The linear chain (active inhibitor) is favoured at low pH, whereas the inactive cyclic compound is favoured at high pH.…”

Section: Slow Tight-binding Inhibitorsmentioning

confidence: 99%

The Therapeutic Potential of Inhibitors of Dipeptidyl Peptidase IV (DPP IV) and Related Proline-Specific Dipeptidyl Aminopeptidases

Augustyns¹,

Veken²,

Senten³

et al. 2005

CMC

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In this review the structural and functional aspects of dipeptidyl peptidase IV (DPP IV) will be described, and the therapeutic potential of DPP IV inhibitors will be highlighted. DPP IV will be situated in clan SC, a group of serine proteases that contains several proline specific peptidases. Structural aspects of DPP IV and its interaction with different types of inhibitors are recently revealed by the publication of several crystal structures. Especially the design and development of new DPP IV inhibitors based on the three-dimensional structure, substrate specificity and catalytic mechanism will be discussed. In the last years there was an important development of new pyrrolidine-2-nitriles with very promising therapeutic properties for the treatment of type 2 diabetes. The role of DPP IV in peptide metabolism of members of the PACAP/glucagon peptide family, neuropeptides and chemokines has been thoroughly investigated during recent years. This is directly related to the promising therapeutic potential of DPP IV inhibitors in the treatment of type 2 diabetes and in the treatment of immunological disorders. Several inhibitors are currently under investigation in clinical trials for the treatment of type 2 diabetes and represent a new class of drugs for the treatment of this disease.

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“…2,3 Since then, DPPIV has been shown to play a key role in regulating the incretin hormones GLP-1 and GIP and has become a validated target for the treatment of type 2 diabetes. 4,5 Two DPPIV inhibitors, sitagliptin and saxagliptin, have been approved to date by the FDA, vildagliptin has been approved in Europe, and several others are in late stage clinical trials.…”

Section: ' Introductionmentioning

confidence: 99%

Pro-Soft Val-boroPro: A Strategy for Enhancing in Vivo Performance of Boronic Acid Inhibitors of Serine Proteases

et al. 2011

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Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at physiological pH, which attenuates its inhibitory potency >100-fold, which is a "soft drug" effect. Here we show that this phenomenon can be exploited to create prodrugs with unique properties and potential for selective in vivo targeting. Enzyme-mediated release delivers 1 to the target in the active form at physiological pH; cyclization attenuates systemic pharmacological effects from subsequent diffusion. This "pro-soft" design is demonstrated with a construct activated by and targeted to DPPIV, including in vivo results showing improved antihyperglycemic activity and reduced toxicity relative to 1. Pro-soft derivatives of 1 can help to illuminate the mechanisms underlying the three biological activities, or to help localize 1 at a tumor and thereby lead to improved anticancer agents with reduced toxicity. The design concept can also be applied to a variety of other boronic acid inhibitors.

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Immunosuppresive boronic acid dipeptides: correlation between conformation and activity

Cited by 44 publications

References 0 publications

Inhibition of dipeptidyl peptidase IV by fluoroolefin-containingN-peptidyl-O-hydroxylamine peptidomimetics

Inhibition of dipeptidyl peptidase IV by fluoroolefin-containingN-peptidyl-O-hydroxylamine peptidomimetics

The Therapeutic Potential of Inhibitors of Dipeptidyl Peptidase IV (DPP IV) and Related Proline-Specific Dipeptidyl Aminopeptidases

Pro-Soft Val-boroPro: A Strategy for Enhancing in Vivo Performance of Boronic Acid Inhibitors of Serine Proteases

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