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1.
J Med Chem ; 67(12): 10306-10320, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38872300

ABSTRACT

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.


Subject(s)
Drug Design , Receptors, Vitronectin , Animals , Rats , Humans , Receptors, Vitronectin/antagonists & inhibitors , Receptors, Vitronectin/metabolism , Structure-Activity Relationship , Liver Cirrhosis/drug therapy , Models, Molecular , Drug Discovery , Rats, Sprague-Dawley , Male , Crystallography, X-Ray , Benzimidazoles/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis
2.
J Med Chem ; 67(6): 4376-4418, 2024 Mar 28.
Article in English | MEDLINE | ID: mdl-38488755

ABSTRACT

In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes the synthetic approach demonstrated on largest scale for each new drug based on patent or primary literature. The synthetic routes highlight practical methods to construct molecules, sometimes on the manufacturing scale, to access the new drugs. Ten additional drugs approved in 2021 and one approved in 2020 are included that were not covered in the previous year's review.


Subject(s)
Drug Approval , United States , Japan , United States Food and Drug Administration , China
3.
Bioorg Med Chem ; 103: 117577, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38518735

ABSTRACT

Small-molecule antivirals that prevent the replication of the SARS-CoV-2 virus by blocking the enzymatic activity of its main protease (Mpro) are and will be a tenet of pandemic preparedness. However, the peptidic nature of such compounds often precludes the design of compounds within favorable physical property ranges, limiting cellular activity. Here we describe the discovery of peptide aldehyde Mpro inhibitors with potent enzymatic and cellular antiviral activity. This structure-activity relationship (SAR) exploration was guided by the use of calculated hydration site thermodynamic maps (WaterMap) to drive potency via displacement of waters from high-energy sites. Thousands of diverse compounds were designed to target these high-energy hydration sites and then prioritized for synthesis by physics- and structure-based Free-Energy Perturbation (FEP+) simulations, which accurately predicted biochemical potencies. This approach ultimately led to the rapid discovery of lead compounds with unique SAR that exhibited potent enzymatic and cellular activity with excellent pan-coronavirus coverage.


Subject(s)
COVID-19 , Coronavirus 3C Proteases , SARS-CoV-2 , Humans , Peptides/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , Molecular Docking Simulation
4.
Science ; 382(6671): eabo7201, 2023 11 10.
Article in English | MEDLINE | ID: mdl-37943932

ABSTRACT

We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.


Subject(s)
COVID-19 Drug Treatment , Coronavirus 3C Proteases , Coronavirus Protease Inhibitors , Drug Discovery , SARS-CoV-2 , Humans , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Molecular Docking Simulation , Coronavirus Protease Inhibitors/chemical synthesis , Coronavirus Protease Inhibitors/chemistry , Coronavirus Protease Inhibitors/pharmacology , Structure-Activity Relationship , Crystallography, X-Ray
5.
J Med Chem ; 66(15): 10150-10201, 2023 08 10.
Article in English | MEDLINE | ID: mdl-37528515

ABSTRACT

Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.


Subject(s)
Drug Design , Humans , Pharmaceutical Preparations , Immunoconjugates/chemistry
6.
J Med Chem ; 65(14): 9607-9661, 2022 07 28.
Article in English | MEDLINE | ID: mdl-35833579

ABSTRACT

New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.


Subject(s)
Drug Design , Immunoconjugates , Humans
7.
J Med Chem ; 64(7): 3604-3657, 2021 04 08.
Article in English | MEDLINE | ID: mdl-33783211

ABSTRACT

New drugs introduced to the market are privileged structures having affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This review is part of a continuing series presenting the most likely process-scale synthetic approaches to 40 NCEs approved for the first time anywhere in the world in 2019.


Subject(s)
Chemistry Techniques, Synthetic/methods , Organic Chemicals/chemical synthesis , Pharmaceutical Preparations/chemical synthesis , Animals , Humans
8.
Chembiochem ; 21(6): 789-792, 2020 03 16.
Article in English | MEDLINE | ID: mdl-31552694

ABSTRACT

The prevalence of life-threatening, drug-resistant microbial infections has challenged researchers to consider alternatives to currently available antibiotics. Teixobactin is a recently discovered "resistance-proof" antimicrobial peptide that targets the bacterial cell wall precursor lipid II. In doing so, teixobactin exhibits potent antimicrobial activity against a wide range of Gram-positive organisms. Herein we demonstrate that teixobactin and several structural analogues are capable of binding lipid II from both Gram-positive and Gram-negative bacteria. Furthermore, we show that when combined with known outer membrane-disrupting peptides, teixobactin is active against Gram-negative organisms.


Subject(s)
Anti-Bacterial Agents/pharmacology , Cell Wall/drug effects , Depsipeptides/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Uridine Diphosphate N-Acetylmuramic Acid/analogs & derivatives , Anti-Bacterial Agents/chemistry , Binding Sites/drug effects , Depsipeptides/chemistry , Microbial Sensitivity Tests , Molecular Conformation , Uridine Diphosphate N-Acetylmuramic Acid/antagonists & inhibitors
9.
J Med Chem ; 60(17): 7591-7604, 2017 09 14.
Article in English | MEDLINE | ID: mdl-28857558

ABSTRACT

A series of 180 vinblastine 20' amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm , Neoplasms/drug therapy , Vinblastine/analogs & derivatives , Vinblastine/pharmacology , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Drug Resistance, Multiple , Humans , Neoplasms/metabolism , Structure-Activity Relationship , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Vinblastine/chemical synthesis
10.
Proc Natl Acad Sci U S A ; 113(35): 9691-8, 2016 08 30.
Article in English | MEDLINE | ID: mdl-27512044

ABSTRACT

Approaches to improving the biological properties of natural products typically strive to modify their structures to identify the essential pharmacophore, or make functional group changes to improve biological target affinity or functional activity, change physical properties, enhance stability, or introduce conformational constraints. Aside from accessible semisynthetic modifications of existing functional groups, rarely does one consider using chemical synthesis to add molecular complexity to the natural product. In part, this may be attributed to the added challenge intrinsic in the synthesis of an even more complex compound. Herein, we report synthetically derived, structurally more complex vinblastines inaccessible from the natural product itself that are a stunning 100-fold more active (IC50 values, 50-75 pM vs. 7 nM; HCT116), and that are now accessible because of advances in the total synthesis of the natural product. The newly discovered ultrapotent vinblastines, which may look highly unusual upon first inspection, bind tubulin with much higher affinity and likely further disrupt the tubulin head-to-tail α/ß dimer-dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid, and extended C20' urea along the adjacent continuing protein-protein interface. In this case, the added molecular complexity was used to markedly enhance target binding and functional biological activity (100-fold), and likely represents a general approach to improving the properties of other natural products targeting a protein-protein interaction.


Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Chemistry Techniques, Synthetic , Tubulin Modulators/chemical synthesis , Tubulin/chemistry , Urea/chemistry , Vinblastine/analogs & derivatives , Antineoplastic Agents, Phytogenic/pharmacology , Binding Sites , Biological Products/chemistry , Cell Line, Tumor , Drug Design , HCT116 Cells , Humans , Inhibitory Concentration 50 , Protein Binding , Protein Interaction Domains and Motifs , Protein Multimerization , Protein Structure, Secondary , Structure-Activity Relationship , Tubulin Modulators/pharmacology , Vinblastine/chemical synthesis , Vinblastine/chemistry , Vinblastine/pharmacology , Vinca Alkaloids/chemistry
11.
PLoS One ; 11(4): e0153912, 2016.
Article in English | MEDLINE | ID: mdl-27101010

ABSTRACT

BACKGROUND: Cyclic acyldepsipeptides (ADEPs) are a novel class of antibacterial agents, some of which (e.g., ADEP 4) are highly active against Gram-positive bacteria. The focus of these in vivo studies is ADEP B315, a rationally designed compound that has the most potent in vitro activity of any ADEP analog reported to date. METHODS: In vivo efficacy experiments were performed using lethal intraperitoneal mice infection models with a methicillin-sensitive S. aureus (MSSA) and a methicillin-resistant (MRSA) strain. The infected mice were treated with ADEP B315, a des-methyl analog of ADEP 4, vancomycin, or the vehicle used for the ADEPs and their survival was assessed daily. A subset of MSSA-infected mice was sacrificed soon after inoculation and the bacterial burden was measured in their livers and spleens. The toxicity of ADEP B315 was assessed in viability assays using human whole blood cultures. RESULTS: In the MSSA experiments, all mice treated with the vehicle succumbed to the infection within 24 hours. All tested compounds were effective in prolonging survival of infected mice (p<0.001). Mice treated with ADEP B315 had a 39% survival rate by 10 days compared to 7% survival in mice treated with a des-methyl ADEP 4 analog (p = 0.017). Survival of the infected mice treated with ADEP B315 was comparable to those treated with vanocmycin (p = 0.12) at the same dose. Further, bacterial burden in the liver and spleen was significantly lower in mice treated with ADEP B315 compared to controls. In the MRSA experiments, ADEP B315 was able to significantly prolong survival compared to mice treated with either the vehicle (p = 0.001) or vancomycin (p = 0.007). ADEP B315 exhibited no significant toxicity in human whole blood cultures at concentrations up to 25 µg/ml. CONCLUSIONS: ADEP B315 is safe and can cure mice that have lethal infections of methicillin-sensitive and -resistant strains of S. aureus.


Subject(s)
Methicillin-Resistant Staphylococcus aureus/isolation & purification , Peptides, Cyclic/therapeutic use , Staphylococcal Infections/drug therapy , Animals , Female , Mice , Peptides, Cyclic/chemistry
12.
Chembiochem ; 16(13): 1875-1879, 2015 Sep 07.
Article in English | MEDLINE | ID: mdl-26147653

ABSTRACT

The cyclic acyldepsipeptide (ADEP) antibiotics act by binding the ClpP peptidase and dysregulating its activity. Their exocyclic N-acylphenylalanine is thought to structurally mimic the ClpP-binding, (I/L)GF tripeptide loop of the peptidase's accessory ATPases. We found that ADEP analogues with exocyclic N-acyl tripeptides or dipeptides resembling the (I/L)GF motif were weak ClpP activators and had no bioactivity. In contrast, ADEP analogues possessing difluorophenylalanine N-capped with methyl-branched acyl groups-like the side chains of residues in the (I/L)GF motifs-were superior to the parent ADEP with respect to both ClpP activation and bioactivity. We contend that the ADEP's N-acylphenylalanine moiety is not simply a stand-in for the ATPases' (I/L)GF motif; it likely has physicochemical properties that are better suited for ClpP binding. Further, our finding that the methyl-branching on the acyl group of the ADEPs improves activity opens new avenues for optimization.

13.
ACS Infect Dis ; 1(1): 53-8, 2015 Jan 09.
Article in English | MEDLINE | ID: mdl-27620145

ABSTRACT

Membrane protein-mediated drug efflux is a phenomenon that compromises our ability to treat both infectious diseases and cancer. Accordingly, there is much interest in the development of strategies for suppression of the mechanisms by which therapeutic agents are effluxed. Here, using resistance to the cyclic acyldepsipeptide (ADEP) antibacterial agents as a model, we demonstrate a new counter-efflux strategy wherein a fragment of an actively exported bioactive compound competitively interferes with its efflux and potentiates its activity. A fragment comprising the N-heptenoyldifluorophenylalanine side chain of the pharmacologically optimized ADEPs potentiates the antibacterial activity of the ADEPs against actinobacteria to a greater extent than reserpine, a well-known efflux inhibitor. Beyond their validation of a new approach to studying molecular recognition by drug efflux pumps, our findings have important implications for killing Mycobacterium tuberculosis with ADEPs and reclaiming the efficacies of therapeutic agents whose activity has been compromised by efflux pumps.

14.
Proc Natl Acad Sci U S A ; 111(43): E4587-95, 2014 Oct 28.
Article in English | MEDLINE | ID: mdl-25267638

ABSTRACT

Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave small peptides, the Mycobacterium tuberculosis enzyme consists of discrete ClpP1 and ClpP2 heptamers that require a AAA+ partner and protein-substrate delivery or a peptide agonist to stabilize assembly of the active tetradecamer. Here, we show that cyclic acyldepsipeptides (ADEPs) and agonist peptides synergistically activate ClpP1P2 by mimicking AAA+ partners and substrates, respectively, and determine the structure of the activated complex. Our studies establish the basis of heteromeric ClpP1P2 assembly and function, reveal tight coupling between the conformations of each ring, show that ADEPs bind only to one ring but appear to open the axial pores of both rings, provide a foundation for rational drug development, and suggest strategies for studying the roles of individual ClpP1 and ClpP2 rings in Clp-family proteolysis.


Subject(s)
Adenosine Triphosphatases/metabolism , Bacterial Proteins/chemistry , Models, Biological , Mycobacterium tuberculosis/enzymology , Peptide Hydrolases/metabolism , Protein Subunits/chemistry , Bacterial Proteins/metabolism , Catalytic Domain , Crystallography, X-Ray , Enzyme Activation , Enzyme Stability , Peptides, Cyclic/chemistry , Peptides, Cyclic/metabolism , Protein Binding , Protein Multimerization , Protein Subunits/metabolism , Substrate Specificity
15.
Chembiochem ; 15(15): 2216-20, 2014 Oct 13.
Article in English | MEDLINE | ID: mdl-25212124

ABSTRACT

The development of new antibacterial agents, particularly those with unique biological targets, is essential to keep pace with the inevitable emergence of drug resistance in pathogenic bacteria. We identified the minimal structural component of the cyclic acyldepsipeptide (ADEP) antibiotics that exhibits antibacterial activity. We found that N-acyldifluorophenylalanine fragments function via the same mechanism of action as ADEPs, as evidenced by the requirement of ClpP for the fragments' antibacterial activity, the ability of fragments to activate Bacillus subtilis ClpP in vitro, and the capacity of an N-acyldifluorophenylalanine affinity matrix to capture ClpP from B. subtilis cell lysates. N-acyldifluorophenylalanine fragments are much simpler in structure than the full ADEPs and are also highly amenable to structural diversification. Thus, the stage has been set for the development of non-peptide activators of ClpP that can be used as antibacterial agents.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Depsipeptides/pharmacology , Endopeptidase Clp/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Bacillus subtilis/enzymology , Depsipeptides/chemistry , Dose-Response Relationship, Drug , Endopeptidase Clp/chemistry , Endopeptidase Clp/metabolism , Enzyme Activation/drug effects , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
16.
Bioorg Med Chem ; 22(17): 4836-47, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25087050

ABSTRACT

Human polyoma- and papillomaviruses are non-enveloped DNA viruses that cause severe pathologies and mortalities. Under circumstances of immunosuppression, JC polyomavirus causes a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML) and the BK polyomavirus is the etiological agent of polyomavirus-induced nephropathy and hemorrhagic cystitis. Human papillomavirus type 16, another non-enveloped DNA virus, is associated with the development of cancers in tissues like the uterine cervix and oropharynx. Currently, there are no approved drugs or vaccines to treat or prevent polyomavirus infections. We recently discovered that the small molecule Retro-2(cycl), an inhibitor of host retrograde trafficking, blocked infection by several human and monkey polyomaviruses. Here, we report diversity-oriented syntheses of Retro-2(cycl) and evaluation of the resulting analogs using an assay of human cell infections by JC polyomavirus. We defined structure-activity relationships and also discovered analogs with significantly improved potency as suppressors of human polyoma- and papillomavirus infection in vitro. Our findings represent an advance in the development of drug candidates that can broadly protect humans from non-enveloped DNA viruses and toxins that exploit retrograde trafficking as a means for cell entry.


Subject(s)
Axonal Transport/drug effects , JC Virus/drug effects , Neurons/drug effects , Neurons/virology , Papillomaviridae/drug effects , Quinazolines/pharmacology , Virus Internalization/drug effects , Cell Line , Dose-Response Relationship, Drug , Humans , JC Virus/physiology , Molecular Structure , Papillomaviridae/physiology , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity Relationship
17.
J Am Chem Soc ; 136(5): 1922-9, 2014 Feb 05.
Article in English | MEDLINE | ID: mdl-24422534

ABSTRACT

The cyclic acyldepsipeptide (ADEP) antibiotics are a new class of antibacterial agents that kill bacteria via a mechanism that is distinct from all clinically used drugs. These molecules bind and dysregulate the activity of the ClpP peptidase. The potential of these antibiotics as antibacterial drugs has been enhanced by the elimination of pharmacological liabilities through medicinal chemistry efforts. Here, we demonstrate that the ADEP conformation observed in the ADEP-ClpP crystal structure is fortified by transannular hydrogen bonding and can be further stabilized by judicious replacement of constituent amino acids within the peptidolactone core structure with more conformationally constrained counterparts. Evidence supporting constraint of the molecule into the bioactive conformer was obtained by measurements of deuterium-exchange kinetics of hydrogens that were proposed to be engaged in transannular hydrogen bonds. We show that the rigidified ADEP analogs bind and activate ClpP at lower concentrations in vitro. Remarkably, these compounds have up to 1200-fold enhanced antibacterial activity when compared to those with the peptidolactone core structure common to two ADEP natural products. This study compellingly demonstrates how rational modulation of conformational dynamics may be used to improve the bioactivities of natural products.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Depsipeptides/chemistry , Depsipeptides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Crystallography, X-Ray , Depsipeptides/chemical synthesis , Enterococcus faecalis/drug effects , Hydrogen Bonding , Microbial Sensitivity Tests , Protein Conformation , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Structure-Activity Relationship
18.
J Org Chem ; 76(24): 10279-85, 2011 Dec 16.
Article in English | MEDLINE | ID: mdl-22044401

ABSTRACT

Isocyanoacetates are uniquely reactive compounds characterized by an ambivalent isocyano functional group and an enolizable α-carbon. It is widely believed that chiral α-substituted isocyanoacetates are configurationally unstable in some synthetically useful isocyanide-based multicomponent reactions. Herein, we demonstrate that chiral isocyanoacetates can be used with minimal to negligible epimerization in a variety of canonical Ugi four-component condensations as well as Joullié-Ugi three-component condensations, reactions that are particularly useful for constructing complex peptide structures in a single synthetic operation.

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