The gut microbiome is a malleable microbial community that can remodel in response to various factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic D,L-α-peptides that remodeled the Western diet (WD) gut microbiome toward the low-fat-diet microbiome state. Daily oral administration of the peptides in WD-fed LDLr-/- mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including interleukin-6, tumor necrosis factor-α and interleukin-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.

T year, ACS Medicinal Chemistry Letters celebrates its 10th anniversary. To recognize this occasion, we are publishing a Special Issue entitled “Medicinal Chemistry: From Targets to Therapies”. Much has happened since our original call in July 2019 for contributions to this anniversary issue. Indeed, the coronavirus SARS-CoV has overtaken the world amidst a global pandemic. Consequently, antiviral research and vaccine development and production have been catapulted into the spotlight. In the face of the problem of viral and bacterial resistance, there is a pressing need for enhanced, sustained research on anti-infective agents. At the same time, pharmaceutical treatments in many other fields are still urgently needed. Medicinal Chemistry is called upon to answer gaps and inequalities in addressing public health needs, more than ever on a moment’s notice. We are honored to be able to present expert articles covering a wide diversity of topics from some of the most prominent and creative research groups. These papers address numerous therapeutic areas, such as autoimmune and inflammatory diseases, anxiety disorders, bacterial and viral infections, cachexia and anorexia, cancer, gout, ischemia, pain, metabolic disorders, chronic obstructive pulmonary disorder (COPD), asthma, rheumatoid arthritis, psoriasis, lysosomal storage disorders, and neurodegenerative diseases. Thirty-three Letters, two Viewpoints, three Innovations and three Patent Highlights have been contributed by prominent players in their respective fields. Letters cover subjects such as cyclooxygenase 1 detection (by Malerba et al.), FAK-targeting PROTACs (Gao et al.), a chimeric inhibitor of macrophage migration inhibitory factor (Cirillo et al.), Bruton’s tyrosine kinase (BTK) inhibitors (Zhang et al.), oximes for acetylcholine esterase reactivation (Gambino et al.), Zika virus inhibitors (Coluccia et al.), phosphodiesterase 4B (PDE4B) inhibitors (Vadukoot et al.), sirtuin 1−3 inhibition (Rajabi et al.), analogs of the Gram-negative antibiotic zafirlukast (Howard et al.), screens for hepatitis B (HBV) antiviral discovery (Hartman et al.), A3 adenosine receptor (A3AR) agonists (Tosh et al.), fibroblast growth factor receptor 4 (FGFR4) inhibitors (Liu et al.), inactivators of γ-aminobutyric acid aminotransferase (GABA-AT) (Shen et al.), bitopic agonists of dopamine D3R (Battiti et al.), 15 harmaline analogs as COX-2 inhibitors (Uddin et al.), imaging approaches in osteoarthritis (Uddin et al.), HIV-1 protease inhibitors (Ghosh et al.), brain-permeable tafamidis analogs (Sinha et al.), melanocortin receptor antagonists (Ericson et al.), choline antimetabolites (Bollenbach et al.), bromodomain and extra-terminal (BET) inhibitors (Altenburg et al.), raltegravir photoaffinity labels (Pala et al.), selective orexin-1 antagonists (Prev́ille et al.), folate receptor targeting agents (Jin et al.), intracellular peptide delivery (Ng et al.), gibberellin-based inhibitors of NF-kB (Annand et al.), agonists of a cannabinoid-activated GPCR (Schoeder et al.), ceramide galactosyltransferase enzyme inhibitors (Thurairatnam et al.), thermoresponsive perfluorocarbon hydrogels (Herneisey et al.), a sigma-2 receptor agonist that could be effective in COVID-19 (Colabufo et al.), a uric acid uptake inhibitor (Uda et al.), and cationic photosensitizers (Mazumdar et al.). A Featured Letter describes the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that can serve both as a tool compound as well as a lead structure for apoptosis-inducing anticancer drugs (Wang et al.). Viewpoints provide perspectives on isosteric replacements of anilines (Sodano et al.) and deuterium-switches (DeWitt et al.). Innovations demonstrate the utility of phenotypic drug discovery strategies (Childers et al.), allosteric modulators (Han et al.), and brain-penetrant EGFR tyrosine kinase inhibitors (Tsang et al.). The Patent Highlights discuss the development of dual specificity tyrosine phosphorylation regulated kinase-1 A (DYRK1A) inhibitors (Kargbo), a SMARCA2/4 PROTAC (Kargbo), and C-RAF and EGFR combination therapy (Kargbo). Our 10-year anniversary issue includes contributions from authors in Australia, China, Denmark, Germany, Italy, Japan, Poland, Singapore, Taiwan, and the USA, reflecting the truly international nature of contemporary Science. As an ensemble, these articles showcase the diversity and state-of-the-art of medicinal chemistry in 2020, as well as implications for future therapeutic developments. Bruce E. Maryanoff orcid.org/0000-0003-3590-2357 Peter Wipf orcid.org/0000-0001-7693-5863

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTEditorial on First-Time Disclosures of Clinical CandidatesBruce E. MaryanoffBruce E. MaryanoffDepartment of Chemistry, The Scripps Research InstituteMore by Bruce E. Maryanoffhttp://orcid.org/0000-0003-3590-2357Cite this: J. Med. Chem. 2018, 61, 13, 5449Publication Date (Web):May 21, 2018Publication History Published online21 May 2018Published inissue 12 July 2018https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00739https://doi.org/10.1021/acs.jmedchem.8b00739editorialACS PublicationsCopyright © 2018 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views2821Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (213 KB) Get e-AlertscloseSUBJECTS:Materials,Medicinal chemistry,Pharmaceuticals Get e-Alerts

There is great interest in developing new modes of therapy for atherosclerosis to treat coronary heart disease and stroke, particularly ones that involve modulation of high-density lipoproteins (HDLs). Here, we describe a new supramolecular chemotype for altering HDL morphology and function. Guided by rational design and SAR-driven peptide sequence enumerations, we have synthesized and determined the HDL remodeling activities of over 80 cyclic d,l-α-peptides. We have identified a few distinct sequence motifs that are effective in vitro in remodeling human and mouse plasma HDLs to increase the concentration of lipid-poor pre-beta HDLs, which are key initial acceptors of cholesterol in the reverse cholesterol transport (RCT) process, and concomitantly promote cholesterol efflux from macrophage cells. Functional assays with various control peptides, such as scrambled sequences, linear and enantiomeric cyclic peptide variants, and backbone-modified structures that limit peptide self-assembly, provide strong support for the supramolecular mode of action. Importantly, when the lead cyclic peptide c[wLwReQeR] was administered to mice (ip), it also promoted the formation of small, lipid-poor HDLs in vivo, displayed good plasma half-life (∼6 h), did not appear to have adverse side effects, and exerted potent anti-inflammatory effects in an acute in vivo inflammation assay. Given that previously reported HDL remodeling peptides have been based on α-helical apoA-I mimetic architectures, the present study, involving a new structural class, represents a promising step toward new potential therapeutics to combat atherosclerosis.

ADVERTISEMENT RETURN TO ISSUEPREVViewpointNEXTDeuterated Drug Molecules: Focus on FDA-Approved DeutetrabenazinePublished as part of the Biochemistry series "Biochemistry to Bedside"Sheila H. DeWitt† and Bruce E. Maryanoff*‡§View Author Information† DeuteRx LLC, 300 Brickstone Square, Suite 201, Andover, Massachusetts 01810, United States‡ Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States§ Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States*E-mail: [email protected]Cite this: Biochemistry 2018, 57, 5, 472–473Publication Date (Web):November 21, 2017Publication History Received9 August 2017Published online21 November 2017Published inissue 6 February 2018https://pubs.acs.org/doi/10.1021/acs.biochem.7b00765https://doi.org/10.1021/acs.biochem.7b00765editorialACS PublicationsCopyright © 2017 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views14952Altmetric-Citations99LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (271 KB) Get e-AlertscloseSUBJECTS:Hydrogen isotopes,Molecular structure,Molecules,Pharmaceuticals,Reaction mechanisms Get e-Alerts

The role of phenotypic assessment in drug discovery is discussed, along with the discovery and development of TOPAMAX (topiramate), a billion-dollar molecule for the treatment of epilepsy and migraine.

Heart disease is the number one killer worldwide, and is responsible for nearly a third of all deaths in the USA. The principal cause of heart disease is lipid accumulation in the arteries with attendant deposition of atherosclerotic plaque, which is comprised mainly of lipids, cholesterol, calcium salts, cells, and cellular debris. Atherosclerosis can be treated by reducing low-density lipoproteincholesterol (LDL-C) via administration of statin drugs. High-density lipoproteins (HDLs) appear to protect against atherosclerosis, such that an increase in their levels and function is desirable. HDL particles, ranging in size from 7-13 nm, are in a constant state of dynamic flux, where the large particles convert into smaller particles, or release free apoA-I. HDL particles accept cholesterol and lipids from peripheral cells and plaques for elimination in the liver (Reverse Cholesterol Transport). The antiatherogenic action of HDL is related to the major structural protein, apolipoprotein A-I (apoA-I), a 243-mer in humans that is comprised of 10 amphiphilic -helices [1]. ApoA-I mimetic peptides are generally amphiphilic -helices that can boost levels of cholesterol-mobilizing, HDL-like particles or improve the functional properties of such particles [1]. We have been involved in the design, synthesis, and functional characterization of novel molecules that mimic apoA-I based on the multivalent presentation of 23-mer and 16-mer amphiphilic, α-helical peptides [2]. Some of these derivatives were athero-preventive in a key mouse model on i.p. and oral (!) administration [3]. Results from this work led us to explore amphiphilic cyclic DL--peptides that could self-assemble into amphiphilic nanotubes.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTOur Scope Expansion to Include BiologicsBruce E. Maryanoff and Donna M. HurynView Author Information Department of Chemistry, The Scripps Research Institute Department of Chemistry, University of Pennsylvania University of Pittsburgh Chemical Diversity Center (UP-CDC)Cite this: ACS Med. Chem. Lett. 2015, 6, 3, 227Publication Date (Web):March 12, 2015Publication History Published online12 March 2015Published inissue 12 March 2015https://pubs.acs.org/doi/10.1021/acsmedchemlett.5b00063https://doi.org/10.1021/acsmedchemlett.5b00063editorialACS PublicationsCopyright © 2015 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views632Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (121 KB) Get e-AlertscloseSUBJECTS:Drug discovery,Immunotherapy,Molecules,Pharmaceuticals,Therapeutics Get e-Alerts

We have observed that molecular constructs based on multiple apoA-I mimetic peptides attached to a branched scaffold display promising anti-atherosclerosis functions in vitro. Building on these promising results, we now describe chronic in vivo studies to assess anti-atherosclerotic efficacy of HDL-like nanoparticles assembled from a trimeric construct, administered over 10 weeks either ip or orally to LDL receptor-null mice. When dosed ip, the trimer-based nanolipids markedly reduced plasma LDL-cholesterol levels by 40%, unlike many other apoA-I mimetic peptides, and were substantially atheroprotective. Surprisingly, these nanoparticles were also effective when administered orally at a dose of 75 mg/kg, despite the peptide construct being composed of l-amino acids and being undetectable in the plasma. The orally administered nanoparticles reduced whole aorta lesion areas by 55% and aortic sinus lesion volumes by 71%. Reductions in plasma cholesterol were due to the loss of non-HDL lipoproteins, while plasma HDL-cholesterol levels were increased. At a 10-fold lower oral dose, the nanoparticles were marginally effective in reducing atherosclerotic lesions. Intriguingly, analogous results were obtained with nanolipids of the corresponding monomeric peptide. These nanolipid formulations provide an avenue for developing orally efficacious therapeutic agents to manage atherosclerosis.

Certain amphipathic α-helical peptides can functionally mimic many of the properties of full-length apolipoproteins, thereby offering an approach to modulate high-density lipoprotein (HDL) for combating atherosclerosis. In this Perspective, we summarize the key findings and advances over the past 25 years in the development of peptides that mimic apolipoproteins, especially apolipoprotein A-I (apoA-I). This assemblage of information provides a reasonably clear picture of the state of the art in the apolipoprotein mimetic field, an appreciation of the potential for such agents in pharmacotherapy, and a sense of the opportunities for optimizing the functional properties of HDL.

We describe an approach for engineering peptide-lipid nanoparticles that function similarly to high-density lipoprotein (HDL). Branched, multivalent constructs, bearing multiple 23- or 16-amino-acid peptides, were designed, synthesized, and combined with phospholipids to produce nanometer-scale discoidal HDL-like particles. A variety of biophysical techniques were employed to characterize the constructs, including size exclusion chromatography, analytical ultracentrifuge sedimentation, circular dichroism, transmission electron microscopy, and fluorescence spectroscopy. The nanoparticles functioned in vitro (human and mouse plasma) and in vivo (mice) to rapidly remodel large native HDLs into small lipid-poor HDL particles, which are key acceptors of cholesterol in reverse cholesterol transport. Fluorescent labeling studies showed that the constituents of the nanoparticles readily distributed into native HDLs, such that the peptide constructs coexisted with apolipoprotein A-I (apoA-I), the main structural protein in HDLs. Importantly, nanolipid particles containing multivalent peptides promoted efficient cellular cholesterol efflux and were functionally superior to those derived from monomeric apoA-I mimetic peptides. The multivalent peptide-lipid nanoparticles were also remarkably stable toward enzymatic digestion in vitro and displayed long half-lives and desirable pharmacokinetic profiles in mice, providing a real practical advantage over previously studied linear or tandem helical peptides. Encouragingly, a two-week exploratory efficacy study in a widely used animal model for atherosclerosis research (LDLr-null mice) using nanoparticles constructed from a trimeric peptide demonstrated an exceptional 50% reduction in the plasma total cholesterol levels compared to the control group. Altogether, the studies reported here point to an attractive avenue for designing synthetic, HDL-like nanoparticles, with potential for treating atherosclerosis.

Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.

We extend to you a warm and sunny Aloha in celebration of the 23 rd American Peptide Symposium and the 6 th International Symposium.The meeting theme, Peptides Across the Pacific, embraced the spirit of the scientific and social program.Peptides Across the Pacific encompassed the important role that peptide science currently plays in so many disciplines and explored the potential impact peptides can make in scientific fields that have yet to realize the utility of these wonderful molecules.The scientific program for 2013