macrocyclic peptide / UCB, Merck (MSD) - LARVOL DELTA

Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor. (PubMed, Circulation) - "This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need."

Journal • Dyslipidemia

Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. (PubMed, Lancet Neurol) - P3 | "Zilucoplan treatment showed rapid and clinically meaningful improvements in myasthenia gravis-specific efficacy outcomes, had a favourable safety profile, and was well tolerated, with no major safety findings. Zilucoplan is a new potential treatment option for a broad population of patients with AChR-positive generalised myasthenia gravis. The long-term safety and efficacy of zilucoplan is being assessed in an ongoing open-label extension study."

Journal • P3 data • CNS Disorders • Infectious Disease • Myasthenia Gravis • Novel Coronavirus Disease • Rare Diseases

Subgroup outcomes from RAISE: A randomized, Phase 3 trial of zilucoplan in generalized myasthenia gravis (AAN 2023) - P3 | "Background RAISE (NCT04115293) was a Phase 3, multicenter, double-blind, placebo-controlled study of zilucoplan, a macrocyclic peptide inhibitor of complement C5, that resulted in statistically significant and clinically meaningful improvement in MG-related efficacy endpoints (primary endpoint: MG-ADL score; LS mean change from baseline [CFB] in zilucoplan: −4.39 vs placebo −2.30, difference −2.09, p<0.001), in patients with AChR Ab+ gMG. Conclusions Daily subcutaneous zilucoplan demonstrated consistent improvements in MG-specific efficacy outcomes irrespective of disease severity or duration. Funding: UCB Pharma."

Clinical • P3 data • CNS Disorders • Myasthenia Gravis

Efficacy and safety of the oral PCSK9 inhibitor MK-0616: a phase 2b randomized controlled trial. (PubMed, J Am Coll Cardiol) - P2b | "MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 of up to 60.9% from baseline and was well tolerated over 8 weeks of treatment and an additional 8 weeks of follow up."

Clinical • Journal • P2b data • Dyslipidemia • Metabolic Disorders

Diversifying Amino Acids and Peptides via Deaminative Reductive Cross-Couplings Leveraging High-Throughput Experimentation. (PubMed, J Am Chem Soc) - "Attractive features include ability to transverse scales, tolerance of pharma-relevant (hetero)aryls and biorthogonal functional groups, and the applicability beyond monomeric amino acids to short and macrocyclic peptide substrates. The success of this work relied on high-throughput experimentation to identify complementary reaction conditions that proved critical for achieving the coupling of a broad scope of aryl bromides with a range of amino acid and peptide substrates including macrocyclic peptides."

Journal

Invention of MK-0616 a macrocyclic peptide oral PCSK9 inhibitor (ACS-Sp 2023) - "This presentation will highlight how Merck’s discovery program was enabled by mRNA display screening to identify cyclic peptide starting points, and lead optimization efforts accelerated by our institutional strength in structure-based drug design and innovative medicinal chemistry. We will outline the key structure activity relationship studies culminating in the discovery of MK-0616, and the clinical translation of oral PK/TE/PD in Phase 1 SAD/MAD studies."

Dyslipidemia • Metabolic Disorders

Rapid label-free cell-based Approach Membrane Permeability Assay using MALDI-hydrogen-deuterium exchange mass spectrometry for peptides. (PubMed, Anal Chim Acta) - "The developed methodology, referred to as Cell-based Approach Membrane Permeability Assay (CAMPA), was applied to study an array of 24 diverse peptides including cell-penetrating peptides, stapled and macrocyclic peptides...The CAMPA MALDI-MS analysis was fully automated including MS data processing using internally developed Python scripts. Moreover, CAMPA was demonstrated to be useful for differentiating passive and active cell transportation by using an endocytosis inhibitor in cell incubation media for selected peptides."

Journal

Prevention of Anti-HMGCR Immune-Mediated Necrotising Myopathy by C5 Complement Inhibition in a Humanised Mouse Model. (PubMed, Biomedicines) - "We evaluated zilucoplan, an investigational drug, and a macrocyclic peptide inhibitor of complement component 5 (C5), in humanized mouse models of IMNM. In this latter setting, C5 inhibition did not significantly ameliorate muscle strength. Early administration of zilucoplan prevents the onset of myopathy at the clinical and histological level in a humanized mouse model of IMNM."

Journal • Preclinical • Immunology • Myositis

Accelerated Identification of Cell Active KRAS Inhibitory Macrocyclic Peptides using Mixture Libraries and Automated Ligand Identification System (ALIS) Technology. (PubMed, J Med Chem) - "Additional stability and permeability optimization resulted in the identification of peptide 7 that inhibited pERK activity in a pancreatic cancer cell line. More broadly, this methodology offers an efficient alternative to accelerate the fastidious hit-to-lead optimization of PPI peptide inhibitors."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Bioisostere Effects on the EPSA of Common Permeability-Limiting Groups. (PubMed, ACS Med Chem Lett) - "The EPSA method to measure this quantity has had a substantial impact in medicinal chemistry, providing insight into the conformational and stereoelectronic features that govern the polarity of small molecules, targeted protein degraders, and macrocyclic peptides...Our findings reinforce EPSA's utility in optimizing permeability, highlight bioisosteres within each class that are particularly effective in lowering EPSA and others, which despite widespread use, offer little to no such benefit. Our method for matched-pair identification is generalizable across large compound collections and, thus, may constitute a flexible platform to study the effects of bioisosterism both in EPSA and other in vitro assays."

Journal

Constructing Head-to-Tail Cyclic Peptide DNA-Encoded Libraries Using Two-Directional Synthesis Strategy. (PubMed, Bioconjug Chem) - "To tackle this issue and streamline the synthetic workflow, we report a two-directional synthesis strategy. This method starts from a trifunctional reagent and prepares DNA-linked macrocyclic peptides of ring size between 15 (5-mer) and 24 (8-mer) via amide bond formation reaction, a common method to create macrocyclic peptides."

Journal

Effects of Bioisosteric Substitution on the Exposed Polar Surface Area (EPSA) of Common Polar Groups (ACS-Sp 2022) - "The EPSA method to measure this quantity has had a major impact in medicinal chemistry, providing insight into the conformational and stereoelectronic features that govern the overall polarity of conventional small molecules, targeted protein degraders, and macrocyclic peptides alike...Our findings highlight bioisosteres within each class that are particularly effective in lowering EPSA and others which, despite widespread use, offer little to no such benefit. Our method for matched-pair identification is generalizable across large compound collections and thus may constitute a flexible platform to study the effects of bioisosterism both in EPSA and other in vitro assays."

Synthetic macrocyclic peptides that target protein-protein interactions: the discovery and early chemistry development of a PCSK9 inhibitor (ACS-Sp 2022) - "The protein-protein interaction between PCSK9 and the low-density lipoprotein receptor which is targeted by these therapies is a large, flat surface, which has made the discovery of orally-bioavailable small molecule inhibitors highly challenging. This talk will introduce the use of macrocyclic peptides to interrupt such protein-protein interactions, and describe the discovery and early chemistry development of such a PCSK9 inhibitor."

Cardiovascular • Dyslipidemia

Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling. (PubMed, Chem Sci) - "This observation should signal to researchers that cationic-mediated cell entry - an approach that has yet to succeed in the clinic despite a long history of attempts - carries significant therapy-limiting safety liabilities. Nonetheless, the cell-active molecules identified here validate a unique inhibitory epitope on KRAS and thus provide valuable molecular templates for the development of therapeutics that are desperately needed to address KRAS-driven cancers - some of the most treatment-resistant human malignancies."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Interrogation of solution conformation of complex macrocyclic peptides utilizing a combined SEC-HDX-MS, circular dichroism, and NMR workflow. (PubMed, Analyst) - "Combined information about solution conformation character and stability across temperatures and co-solvent compositions greatly expedites selection of optimal conditions for NMR analysis. In total, the combination of SEC-HDX-MS, CD, and NMR into a single complementary workflow greatly accelerates conformational analysis of peptides in the drug discovery lead optimization process."

Journal

A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors. (PubMed, J Med Chem) - "These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors."

Journal • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Metabolic Disorders

Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody-Positive Generalized Myasthenia Gravis. (PubMed, Expert Opin Investig Drugs) - "Zilucoplan is a small, subcutaneously administered, macrocyclic peptide that inhibits cleavage of complement component C5 and the subsequent formation of the membrane attack complex. Zilucoplan, a first-of-its-kind cyclic peptide targeting C5, appears to be a therapeutic option for the treatment of gMG based on available pharmacokinetic/pharmacodynamic data and phase 1 and 2 efficacy, safety, and tolerability data with limited long-term follow-up. Zilucoplan use earlier in the treatment paradigm would be suitable in this population should phase 3 efficacy and safety data be equally favorable."

Clinical • Journal • CNS Disorders • Complement-mediated Rare Disorders • Immunology • Myasthenia Gravis

Modulating Protein-Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples. (PubMed, Molecules) - "Some advances to facilitate the permeability of these quite big molecules by conjugation with cell penetrating peptides, and the incorporation of β-amino acid and peptoid structures to improve metabolic stability, are also commented. It is predicted that this field of research could have an important future mission, running in parallel to the discovery of new, relevant PPIs involved in pathological processes."

Journal • Review

Discovery of Molecular Interactions of the Human Melanocortin-4 Receptor (hMC4R) Asp189 (D189) Amino Acid with the Endogenous G-Protein-Coupled Receptor (GPCR) Antagonist Agouti-Related Protein (AGRP) Provides Insights to AGRP's Inverse Agonist Pharmacology at the hMC4R. (PubMed, ACS Chem Neurosci) - "To further test this hypothesis, six D189 mutant hMC4Rs (D189A, D189E, D189N, D189Q, D189S, and D189K) were generated and pharmacologically characterized resulting in the discovery of differences in inverse agonist activity of AGRP and an 11 macrocyclic compound library. These data support the hypothesized interaction between the hMC4R D189 position and Asn114 residue of AGRP and define critical ligand-receptor molecular interactions responsible for the inverse agonist activity of AGRP at the hMC4R."

Journal • Inflammatory Arthritis

Human and mouse PD-L1: similar molecular structure, but different druggability profiles. (PubMed, iScience) - "We also show major differences in druggability between the hPD-L1 and mPD-L1 using therapeutic antibodies, a macrocyclic peptide, and small molecules. Our study indicates that while the amino acid sequence is well conserved between the hPD-L1 and mPD-L1 and overall structures are almost identical, crucial differences determine the interaction with anti-PD-L1 agents, that cannot be easily predicted in silico."

Journal • Immunology • PD-L1

Development of a highly selective Plasmodium falciparum proteasome inhibitor with anti-malaria activity in humanized mice. (PubMed, Angew Chem Int Ed Engl) - "Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the b5 subunit of the Plasmodium falciparum proteasome, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum -infected mice."

Journal • Infectious Disease • Malaria

Cyclotides from Brazilian Palicourea sessilis and Their Effects on Human Lymphocytes. (PubMed, J Nat Prod) - "Their presence within the Violaceae species seems ubiquitous, yet not all members of other families produce these macrocyclic peptides...The toxicity on other nonimmune cells was also assessed. This study reveals that pase cyclotides have potential for applications as immunosuppressants and in immune-related disorders."

Journal

Emerging peptide antibiotics with therapeutic potential. (PubMed, Med Drug Discov) - "This review covers some of the recent progress in the field of peptide antibiotics with a focus on compounds with novel or established mode of action and with demonstrated efficacy in animal infection models. Novel drug discovery approaches, linear and macrocyclic peptide antibiotics, lipopeptides like the polymyxins as well as peptides addressing targets located in the plasma membrane or in the outer membrane of bacterial cells are discussed."

Journal • Review • Complement-mediated Rare Disorders • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Infectious Disease • Oncology • Pneumonia • Respiratory Diseases • Solid Tumor

When Macrocyclic Peptides Meet the Crystal Structure of a Melanocortin Receptor. (PubMed, J Med Chem) - "This work reveals some key factors for the design of a novel generation of selective melanocortin ligands at the MC4 receptor."

Journal

[VIRTUAL] DESIGNED MACROCYCLIC AMYLOIDOGENESIS INHIBITORY PEPTIDE MITIGATES ALZHEIMER’S DISEASE PATHOLOGY IN A MURINE MODEL OF ALZHEIMER’S DISEASE (ADPD 2021) - "We previously showed that designed islet amyloid polypeptide (IAPP)-derived macrocyclic peptides (MCIPs) can act as nanomolar inhibitors against amyloidogenesis in -vitro... Treatment of 5x FAD mice with the 2E peptide mitigates hallmarks of AD pathology such as amyloid burden, behavior deficits, and neuronal damage. These results suggest 2E and related MCIPs are promising treatment candidates for AD."

Preclinical • Alzheimer's Disease • CNS Disorders • APP