Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors

Yang, Chao; Phillips, James G.; Stuckey, Jeanne A.; Bai, Longchuan; Sun, Haiying; Delproposto, James; Brown, William Clay; Chinnaswamy, Krishnapriya

doi:10.1021/acsmedchemlett.6b00299

Cited by 21 publications

(24 citation statements)

References 25 publications

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“…Furthermore, we find that pro-FD is also present in blood samples from healthy donors. Due to the increasing interest in FD as a drug target in autoimmune diseases, it is of central importance to understand the process of pro-FD maturation, because it could suggest novel strategies for therapeutic intervention (61,62).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Factor D Isoforms in Malpuech–Michels–Mingarelli–Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement

Pihl

Jensen

Hansen

et al. 2017

The Journal of Immunology

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Factor D (FD), which is also known as adipsin, is regarded as the first-acting protease of the alternative pathway (AP) of complement. It has been suggested that FD is secreted as a mature enzyme that does not require subsequent activation. This view was challenged when it was shown that mice lacking mannose-binding lectin (MBL)-associated serine protease-1 (MASP-1) and MASP-3 contain zymogenic FD (pro-FD), and it is becoming evident that MASP-3 is implicated in pro-FD maturation. However, the necessity of MASP-3 for pro-FD cleavage has been questioned, because AP activity is still observed in sera from MASP-1/3-deficient Malpuech-Michels-Mingarelli-Carnevale (3MC) patients. The identification of a novel 3MC patient carrying a previously unidentified MASP-3 G665S mutation prompted us to develop an analytical isoelectric focusing technique that resolves endogenous FD variants in complex samples. This enabled us to show that although 3MC patients predominantly contain pro-FD, they also contain detectable levels of mature FD. Moreover, using isoelectric focusing analysis, we show that both pro-FD and FD are present in the circulation of healthy donors. We characterized the naturally occurring 3MC-associated MASP-3 mutants and found that they all yielded enzymatically inactive proteins. Using MASP-3-depleted human serum, serum from 3MC patients, and mice, we found that lack of enzymatically active MASP-3, or complete MASP-3 deficiency, compromises the conversion of pro-FD to FD. In summary, our observations emphasize that MASP-3 acts as an important maturase in the AP of complement, while also highlighting that there exists MASP-3-independent pro-FD maturation in 3MC patients.

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Section: Discussionmentioning

confidence: 99%

Analysis of Factor D Isoforms in Malpuech–Michels–Mingarelli–Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement

Pihl

Jensen

Hansen

et al. 2017

The Journal of Immunology

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“…Various efforts have already been made to develop and clinically investigate factor D inhibitors ( 51 , 95 ). Although some of these efforts have involved taking advantage of structural information to develop highly specific small-molecule inhibitors ( 95 , 96 ), others have evaluated the feasibility of using anti–factor D antibody fragments ( 97 ).…”

Section: Factor D As a Strategic Target In Complement-driven Diseasesmentioning

confidence: 99%

Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway

Barratt

Weitz

2021

Front. Immunol.

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The complement system is central to first-line defense against invading pathogens. However, excessive complement activation and/or the loss of complement regulation contributes to the development of autoimmune diseases, systemic inflammation, and thrombosis. One of the three pathways of the complement system, the alternative complement pathway, plays a vital role in amplifying complement activation and pathway signaling. Complement factor D, a serine protease of this pathway that is required for the formation of C3 convertase, is the rate-limiting enzyme. In this review, we discuss the function of factor D within the alternative pathway and its implication in both healthy physiology and disease. Because the alternative pathway has a role in many diseases that are characterized by excessive or poorly mediated complement activation, this pathway is an enticing target for effective therapeutic intervention. Nonetheless, although the underlying disease mechanisms of many of these complement-driven diseases are quite well understood, some of the diseases have limited treatment options or no approved treatments at all. Therefore, in this review we explore factor D as a strategic target for advancing therapeutic control of pathological complement activation.

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“…For example, crystal structures revealed that buried HBs contribute to the high potency of complement factor D inhibitors. 2 Proteins structures obtained by poor electron density maps might have more overlooked NCIs due to the imperfect refinement process. The electron density map showed that an extensive HB network contributes to the great potency of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, while the loss of this HB network completely eliminates the inhibitory capacity against IDO1.…”

Section: ■ Introductionmentioning

confidence: 99%

Underestimated Noncovalent Interactions in Protein Data Bank

Zhang

Shi

et al. 2019

J. Chem. Inf. Model.

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Noncovalent interactions (NCIs) play essential roles in the structure and function of biomacromolecules. There are various NCIs, e.g., hydrogen bonds (HBs), cation−π and π–π interactions, and ionic bonds, among which HBs are the most widespread and well-studied. By utilizing the ratio of the observed HBs over pseudo HBs (1.0 Å longer than the HB distance criteria without angle constraints), we demonstrated that HBs in both protein–ligand and protein–protein interfaces are overlooked in structures deposited in PDB. After the QM/MM optimization of 12 protein–ligand complexes, we showed that the overlooked HBs could be recovered. With a systematic search in the PDB, we found that the HB number per residue (N HB/R) in proteins decreases as structural resolution becomes lower, implying that HBs are overlooked even today, regardless of the type of refinement approach used. Similarly, cation−π, π–π, and ionic interactions were found to be significantly lost, manifesting the universal underestimation of various NCIs. Considering the vital role of NCIs, it is important to recover the NCIs to facilitate drug design, to explore protein–protein interaction, and to study protein structure and function.

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Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors

Cited by 21 publications

References 25 publications

Analysis of Factor D Isoforms in Malpuech–Michels–Mingarelli–Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement

Analysis of Factor D Isoforms in Malpuech–Michels–Mingarelli–Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement

Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway

Underestimated Noncovalent Interactions in Protein Data Bank

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