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COMMENTARY

Success of in structure–function is a challenge for structure-based therapeutics

Charles N. Serhan*† and Bruce Levy*‡ *Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine and ‡Critical Care and Pulmonary Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

rostaglandin (PG) E2 is almost ubiquitous in humans and evokes potent diverse actions. Utility is the price of its perfec- tion.P PGE is a founding member of the 2 PGs, a class of mediators that belongs to the still growing family of bioactive au- tacoids known as the (1–3). The main classes include enzymatically generated products such as thrombox- anes, , , and EETs, as well as others that are produced via nonenzymatic mechanisms, e.g., isopros- tanes and cyclopentaeone PGs that are increasing in number and appreciation (4, 5). PGE2 regulates key responses in the major human systems including re- productive, gastrointestinal, neuroendo- crine, and immune (Fig. 1). Formed by conversion of via cyclo- oxygenase (COX) and specific synthases, Fig. 1. Diverse actions of PGE2 and selective targeted in inflammation. (Inset) family major enzymatic classes of and pathways (see text for details). PGE2 stereospecifically exerts potent (nano- to micromolar range) - and cell type-selective actions (1–6). The importance of PGs in was from protecting gastrointestinal mucosa electrophoresis that this -soluble brought into view by the discovery of J. to regulating and , activity behaved as an acid. Vane and colleagues (7) that nonsteroi- set a steep challenge for designer drug Bergstro¨m’s main research was in bile dal antiinflammatory drugs (NSAIDs) hunters to achieve, namely selectivity acids and steroids. Because of his exper- like , that at the time were used without unwanted side effects. The find- tise in , von Euler approached him clinically without a known mechanism, ings of Trebino et al. raise hope that to tackle the PG isolation and structural act by inhibiting COX production of new classes of drugs targeting mPGES1 problem (3). Surprisingly, Bergstro¨m PGs and . Although highly can be developed for the treatment of first carried out oxidation effective, the COX inhibitors (both painful chronic inflammatory diseases studies in the mid-1930s and then re- COX-1 and COX-2) of today’s clinics such as rheumatoid arthritis. turned to the area to focus on the struc- are still rather blunt therapies at the PGE2 has a long history of celebrity tural elucidation of these bioactive sub- molecular level, because they not only and many eminent scientists devoted to stances. Along with his formidable team block the formation of individual PGs unlocking its secrets, as it was among of students that included Bengt Borg- but also knock out other ‘‘bystander’’ the first eicosanoids elucidated. U. von stro¨m, Jan Sjo¨vall, and Bengt Samuels- eicosanoids that may be needed to Euler and Sune Bergstro¨m each noted son, they elucidated in 1957 the struc- ␣ maintain homeostasis. This can lead to that in 1933 a British pharmacologist, ture of PGE1 and F1 . It took several unwanted side effects in multiple sys- M. W. Goldblatt, reported that human years to recognize that the PGs were tems, i.e., ulcers and constipation. contained a factor that reduced generated from arachidonic acid. Mass Hence there remains considerable room blood pressure and regulated smooth spectrometry was key to these discover- for improvement in this clinical area. In muscle (1, 3). von Euler trained with ies. It wasn’t until the early 1960s that it this issue of PNAS, Trebino et al. (8) H. H. Dale in England and had, just a was possible to radiolabel arachidonic studied the pathogenesis of - acid, and its complete biosynthetic induced arthritis by using microsomal few years earlier, isolated the bioactive compound P. During systematic scheme quickly followed (2). The PGE PGE synthase-1 (mPGES1) deficient structure is conserved in mammalian mice and demonstrate the contributions studies, von Euler found that extracts of and vesicular contained systems and also is produced by marine of this and PGE2 in chronic in- organisms. Large quantities were found potent blood-pressure-lowering factors flammation and pain. Their results pro- in coral, which proved serendipitous be- from sheep and man that stimulated vide in vivo validation of this new target, cause only small amounts could be iso- taking a significant step toward the smooth muscles and were different from promise of more selective therapeutics. compound P. Importantly, von Euler Precision and selectivity are the mantra discovered that the activities were of See companion article on page 9044. of today’s molecular medicine. In this lipidic character and coined the term †To whom correspondence should be addressed. E-mail: context, the range of PGE2 actions, PG (3). Theorell demonstrated by using [email protected].

www.pnas.org͞cgi͞doi͞10.1073͞pnas.1733589100 PNAS ͉ July 22, 2003 ͉ vol. 100 ͉ no. 15 ͉ 8609–8611 Downloaded by guest on September 30, 2021 lated from mammalian systems, limiting which convert arachidonic acid into en- Can disease- and organ-selective drugs availability for pursuit of biological doperoxide PGH2 that serves as sub- be developed? Trebino et al. (8) ad- roles. PG-related compounds from coral strate (Fig. 1 Inset) for multiple syn- dressed some of these with mice defi- became useful in the preparation of PG thases (1–3). The quest for ‘‘better’’ cient in mPGES1. needed to explore their actions. E. J. NSAIDs with improved therapeutic ben- PGE synthase activity is present in Corey achieved total organic synthesis, efits and fewer side effects remains of both cytosolic and membrane-associated in the late 1960s and early 1970s, and great interest. Indeed, identification of a fractions of cells, and optimal catalytic was then able to supply defined com- second COX isoform and its rise as a activity requires (18, 19). pounds that opened the area and estab- clinical target have certainly given new Cytosolic PGE synthases are functionally lished the many actions (1) we know now generations of inhibitors with improved coupled to COX-1 and ubiquitously ex- in target systems responsive to PGE2 as features over traditional COX inhibitors pressed (20). PGE synthase activity can well as other (Fig. 1). (12), but they are not without their own also be induced by proinflammatory It is in the area of inflammation that shortcomings. stimuli in leukocytes (21). Increased mi- PGE2’s actions are most diverse because Initiated by the innate immune sys- crosomal membrane-associated PGE of the many specialized cell types, com- tem, local inflammation increases micro- synthase activity appears in lipopolysac- plex and sometimes seemingly opposing vascular dilatation and permeability to charide (LPS)-stimulated leukocytes actions that make PGE2 one of the enhance phagocyte entry into sites of with a delayed increase in PGE2 attrib- more generally ‘‘misunderstood’’ eico- microbial invasion or tissue injury. Local utable to coordinate expression and sanoids. This confusion likely reflects warmth, erythema, and swelling result functional coupling with COX-2 (22). differences between endogenous forma- To date, two distinct isoforms of micro- tion and action versus the pharmacology somal PGES are characterized, of adding PGE2 in vitro and in vivo. The Seemingly opposing mPGES1 and -2. mPGES-1 has high findings of Trebino et al. (8) not only catalytic activity relative to mPGES2, bring to the forefront notions of selec- modes of action make and is more ubiquitously expressed (19, tive new therapeutics but also clear 23, 24). Cells from mice deficient in some of the lines of thinking on the prostaglandin E2 mPGES1 display impaired LPS-initiated function of PGE2 biosynthesis in vivo. PGE2 formation, but basal PGE2 PGE2 functions in the reproductive sys- one of the more generation is preserved (25). These tem and yet can produce bronchocon- findings indicate discrete roles for the striction as well as hypertension. It also misunderstood PGE synthases and their isoforms in promotes labor and at- inflammation. tributed to its increased endometrial eicosanoids. The fate of endoperoxide intermedi- biosynthesis. The actions of PGE also ates in the absence of a functional syn- extend to the cardiovascular and im- thase is of interest. A reciprocal rela- mune systems, where PGE2’s ability to from these vascular changes as well as tionship between PGD2 and PGE2 enhance inflammation caused by leuko- from release of chemical substances by formation in tumor necrosis factor trienes as well as inhibit release of me- activated leukocytes that can inadver- (TNF)-exposed peritoneal diators and regulate monocyte-macroph- tently injure peripheral nerves as well as (21) suggests a close relationship be- ages and dendritic cells are current sensitize them, giving ‘‘inflammatory’’ tween COX and PG synthases with reg- research topics (9). It is in this multicel- ulated coupling for generation of spe- pain. PGE2 is generated at sites of in- lular milieu of host defense that the flammation in substantial amounts and cific prostanoids. Trebino et al. (8) did mechanisms of PGE and the ability to can mediate many of the pathologic fea- not observe increases in PGI2 on disrup- specifically regulate its local production tures of inflammation (5). PGE is a tion of mPGES-1; however, alterations can have an important impact in chronic 2 in other levels were not re- potent vasodilator (13) and can act syn- inflammatory diseases. ported. Conversion of PGH to an alter- ergistically with other mediators and 2 Acute inflammation is a protective nate PG, nonenzymatic conversion to chemotaxins to increase microvascular host response to pathogens or injury cyclopentaenone PGs, or the generation permeability (14). In conjunction with that evoke its cardinal signs, namely of novel antiinflammatory products re- heat, redness, swelling, pain, and loss of cytokines, PGE2 is a central mediator of mains unexplored in mPGES1-deficient function (4, 5, 10), that are regulated by febrile responses (15, 16), and intrader- animals. mal PGE2 is hyperalgesic in the periph- eicosanoids (1, 2). Regulators of inflam- In addition to PGE2 phlogistic proper- matory responses are of wide interest, eral nervous system. To affect this wide ties, immunomodulatory roles are also because many of the most prevalent hu- terrain of cellular responses, PGE2 in- reported (26). Distinct from its proin- teracts with specific receptors, termed man illnesses, such as arthritis, asthma, flammatory actions, PGE2 promotes res- and atherosclerosis, involve inflamma- EP1–4, that have a restricted patterns of olution of inflammation (27). In addi- tion. Arthritis alone affects Ͼ40 million expression and -specific actions tion, fibroblasts from individuals Americans, is projected to increase to (reviewed in ref. 17). with pulmonary fibrosis display dimin- Ϸ60 million by 2020, and is the leading Despite extensive investigation estab- ished COX-2 expression and PGE2 (28). cause of work-related disability among lishing important roles for PGE2 in in- Acute inflammation has four potential those over age 65 (11). For centuries, flammation, several questions remain. outcomes: complete resolution, abscess antiinflammatory treatments have been Of the many , which PGE syn- formation, healing by fibrosis, or pro- among the most common therapies used thase is responsible for PGE2 formation gression to chronic inflammation (10). by healers (10). Today’s worldwide sales during inflammation? What is its cell Unlike the early COX-2-derived PGE2 of NSAIDs are Ͼ$6 billion and repre- type distribution? How are specific syn- that has a central role in acute inflam- sent 3–9% of all prescriptions, and, in thases coupled and regulated with mation, COX-2-derived products can the U.S., Ͼ90 million prescriptions (Ͼ$2 COX-1 and -2? Is mPGES1 a more se- promote resolution via the generation of billion) are written annually for these lective target for development of new antiinflammatory lipid mediators, in- drugs (11). NSAIDs inhibit COX(s), antiinflammatory drugs than COX-2? cluding prostanoids (other than PGE2),

8610 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.1733589100 Serhan and Levy Downloaded by guest on September 30, 2021 15-epi-lipoxins, and resolvins (29–31). In a striking protection from collagen- and cardiac function as well as increased the absence of mPGES-1, paw edema induced arthritis, with diminished pan- thrombogenesis (34, 35). Similar reduc- formation and leukocyte accumulation nus formation, preservation of proteo- tions in inflammation with mPGES1 and are reduced in delayed-type hypersensi- glycan at articular surfaces, and less COX-2 knockouts now provide new and tivity. Of interest, injection into bony erosions. Antibodies against type potentially more selective targets for the contralateral paws of immunized, II collagen were detected in both con- new antiinflammatory drug design that Ϫ͞Ϫ mPGES1 mice led to increased trol and the mPGES1-deficient mice, could spare the COX-2-derived pro- leukocyte accumulation without in- but the titers were decreased in resolving lipid mediators. creases in edema (8). These observa- mPGES1-deficient animals. Although In summation, PGE2’s biological ac- tions hint at potential additional coun- profound immunosuppression was not tions are tissue- and organ-specific. The terregulatory roles for the enzyme and present, PGE2 displays pivotal regula- results of Trebino et al., that mice, defi- PGE that may become evident with tory actions on innate and adaptive im- 2 cient in microsomal PGE , have im- further investigations of the kinetics of mune effector cells (9, 30). Toll 4 activa- 2 proved collagen-induced arthritis, are complex inflammatory responses, such tion regulates PGE2 formation by as delayed-type hypersensitivity, which mPGES1 (25), and, hence, further study encouraging and suggest that we are at require prominent contributions from is needed to determine whether decre- the dawn of new classes of therapeutic the adaptive for resolu- ments in its formation in mPGES1- drugs that regulate the eicosanoids’ se- tion (27). In several other models of deficient mice may ultimately lead to nior member, PGE2. Presumably, this inflammation, pharmacologic inhibition adverse effects in the host’s capacity to approach should be better tolerated of COX-2 decreases PGE2, but not leu- resolve acute inflammation or respond with fewer unwanted side effects than kocyte infiltration (29, 32). Moreover, to infectious agents. those drugs that block upstream of spe- eicosanoid generation at sites of inflam- Disruption of mPGES1 displayed a cific PG synthases. It appears that mation is temporally regulated, and the similar phenotype in collagen-induced COX-2 inhibitors can lead to an in- early formation of COX-2-derived PGE2 arthritis as pharmacological inhibition or crease in thrombogenesis and cardiovas- can serve as an inducer of subsequent genetic disruption of COX-2. Although cular disease incidence (34, 35). Trebino antiinflammatory circuits, in part, via its there is evidence for an in vivo link be- et al. (8) emphasize that unwanted side roles in amplifying 15-lipoxygenase ex- tween COX-2 and mPGES1, it does not effects of inhibiting PGE2 generation pression and generation (30). preclude the formation of other COX- might be alleviated by targeting mPGE2 Notably, extensive clinical experience 2–derived products, such as the 15- synthase 1. New classes of drugs with with COX inhibition by NSAIDs has epi-lipoxins or resolvins that display anti- precision are likely to abound. provided patients with analgesia and inflammatory and proresolving proper- antiinflammatory actions, but not dis- ties (31). In addition to disruption of We thank Mary H. Small and Katie ease-remitting properties in rheumatoid these proresolving biosynthetic circuits Gotlinger for expert assistance with this arthritis. for ATL (33) and resolvins (31), inhibi- manuscript and the National Institutes of By targeting mPGES-1-generated tion of COX-2 is associated with several Health for support of the research in our PGE2, Trebino et al. (8) uncovered adverse effects, including impaired renal laboratories.

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