The Borgini Laboratory

Matteo Borgini, PhD A man in a suit standing with arms crossed

Assistant Professor, Chemistry

Research Summary

Dr. Borgini completed his undergraduate studies at the University of Siena, Italy, in 2015 and subsequently earned his Ph.D. in Chemical and Pharmaceutical Sciences under the guidance of Professor Maurizio Botta. Throughout his doctoral research, he focused on synthesizing epigenetic modulators with anticancer properties, developing host protein inhibitors as antiviral compounds, and creating novel antifungal and antibacterial drugs. Following his Ph.D., Dr. Borgini undertook postdoctoral studies with Professor Peter Wipf at the University of Pittsburgh. During this period, he pioneered new methods for accessing fluorinated and 13C-labeled amino acids through C-H functionalization. He also worked on the synthesis of complex heterocyclic compounds using transition-metal catalyzed annulative cleavage of bicyclo[1.1.0]butane dihydroquinolines and dihydropyridines. Additionally, he contributed to the development of mitochondria-targeted PARP-1 inhibitor prodrugs with potential applications in neuroprotection. Currently, Dr. Borgini has embarked on his independent career as an Assistant Professor in Medicinal Chemistry at Augusta University within the Department of Chemistry and Biochemistry. In the Borgini Lab, the focus of Drug Discovery is directed toward finding innovative ways to chemically modulate biological targets that are traditionally deemed "undruggable". The lab aims to advance medicinal chemistry tools, particularly in the realms of Protein-Protein Interaction Inhibitors and Covalent Inhibitors.

Contact Us

The Borgini Lab

Health Sciences Campus

Science & Mathematics Building

GE-3053

706-729-2456

mborgini@augusta.edu

 

Research Interests

The Borgini Lab has deep expertise in the synthesis of peptides and small molecules for therapeutic applications. The lab's key research areas include medicinal chemistry, organic chemistry, and chemical biology.

1. Development of Novel Warheads for Covalent Inhibitors.

Covalent inhibitors have been utilized in medicine for over a century, resulting in more than 50 FDA-approved drugs for treating various conditions, including cancer and infectious diseases. These drugs offer significant advantages over traditional reversible inhibitors, such as prolonged action, reduced dosing frequency, and the ability to target previously "undruggable" proteins. Historically, their development faced obstacles due to concerns about toxicity from non-specific protein modifications and interactions with essential biomolecules. However, recent advancements in synthetic organic and medicinal chemistry have revived interest in covalent inhibitors, leading to the creation of novel warheads with enhanced reactivity and specificity. Our research focuses on developing new acrylamide-type warheads using strain-release transformations, which offer high versatility through adjustable electronic properties and steric configurations near the reactive site. These innovative designs position covalent warheads as crucial elements in determining substrate specificity, opening new avenues for drug discovery and development.

2. Protein-Protein Interaction Inhibitors: Development of Selective Inhibitors of the Master Regulator of Anti-oxidative Responses Nrf2.

Cancer cells often experience oxidative stress due to nutrient deprivation and high ROS levels, prompting them to activate defense mechanisms, including the overactivation of Nrf2. Nrf2, a cytoplasmic transcription factor, normally undergoes proteasomal degradation regulated by KEAP1-mediated ubiquitination, but during oxidative stress, it moves to the nucleus to express antioxidative genes. While Nrf2 is crucial for cell survival and homeostasis, its over-activation can exacerbate diseases. Targeting Nrf2 is challenging due to the transient nature of transcription factors, complicating the development of effective inhibitors. Developing selective Nrf2 inhibitors holds significant potential, as they can disrupt cancer cells' defense mechanisms, making them more vulnerable to anticancer drugs. By inhibiting Nrf2 activity, we aim to enhance the efficacy of existing therapies and potentially overcome drug resistance.

Selected Publications

  • M. Borgini, Q. Huang, P. Chen, S. J. Geib, K. N. Houk, P. Wipf, Rhodium(I)-Catalyzed Annulation of Bicyclo[1.1.0]butyl-Substituted Dihydroquinolines and Dihydropyridines, JACS, Article ASAP, DOI: 10.1021/jacs.4c04081
  • M. Borgini, Ł. Wieteska, C.S. Hinck, T. Krzysiak, A.P. Hinck, P. Wipf. Synthesis of 13C-methyl-labeled amino acids and their incorporation into proteins in mammalian cells. Org Biomol Chem. 2023, 21(46), 9216-9229.
  • M. Borgini, P. Wipf. Synthesis of Veliparib Prodrugs and Determination of Drug-Release-Dependent PARP-1 Inhibition, ACS Medicinal Chemistry Letters, 2023, 14(5), 652-657.
  • M. Borgini, P. Wipf. Stereoselective synthesis of δ-fluorinated isoleucines exploiting consecutive C(sp3)-H bond activations, Tetrahedron, 2022, 120, 132876. Special issue in Honor of Dr. Franziska Schoenebeck.
  • M. Borgini, C. Zamperini, F. Poggialini, L. Ferrante, V. Summa, M. Botta, R. Di Fabio. Synthesis and Antiproliferative Activity of Nitric Oxide-Donor Largazole Prodrugs, ACS Medicinal Chemistry Letters, 2020, 11(5), 846-851.
  • M. Borgini, F. Orofino, G. I. Truglio, L. Balestri, M. Botta. A gram-scale synthesis of a macrocyclic amidinourea with strong antifungal activity through a Fukuyama tri-protected polyamine intermediate, Arkivoc, 2019, 4, 168- 177. Special issue in Honor of Dr. Stephen Hanessian.