Retrocyclins: Antiviral Circular Minidefensins that Protect Against Human Immunodeficiency Virus and Herpes Simplex Viruses
- Technology Benefits
- Small (18 amino acids) Non-hemolytic, and virtually noncytotoxic in vitro. Defined mechanism of action against HIV-1 (entry inhibition). Potentially synergistic with other immune-system components, including alpha defensins,protease inhibitors, reverse transcriptase inhibitors, etc.
- Technology Application
- As topical agents to protect against the acquisition of HIV-1 infection. As topical agents to protect newborns from HSV-2 infection acquired during vaginal deliver. As topical agents to speed the healing of herpes keratitis, corneal ulceration caused by HSV-1. As systemic agents, used alone or in combination (e.g. HAART), to treat established HIV-1 infection. As topical agents to protect against sexually-acquired HSV-2 infections. As topical and systemic agents directed against additional viruses whose entry-related glycoproteins are bound by retrocyclins and their analogues.
- Detailed Technology Description
- Retrocyclins 1 and 2 (also called RC-100 and RC100b) are novel circular peptides discovered by UCLA Researchers. Although they are produced synthetically, their structures are based on nucleotide sequences found in the human genome and/or in mRNA expressed by human bone marrow. Since human theta-defensin genes and retrocyclin bone marrow mRNA contain a premature stop codon in their signal sequence, retrocyclin peptides are probably not produced in humans. However, these peptides are found in certain Old World monkeys, and intact theta defensin genes are also present in lesser apes and orangutans (unpublished). Although the ability of theta defensins to kill bacteria is relatively modest, retrocyclin 1 and especially retrocyclin-2 show impressive activity against three different viral pathogens: human immunodeficiency virus (HIV-1), herpes simplex virus-1 and herpes simplex virus-2 (HSV-2). Although such broad specificity is somewhat reminiscent of interferons, retrocyclins operate as entry inhibitors. Retrocyclin-2 showed activity against a wide library of primary HIV-1 isolates of diverse subtypes, including subtypes A, B, C, CRF01, D, G, and recombinant subtypes. Its effectiveness was not dependent on or restricted by co-receptor (R5, X4 or R5X4) usage. The UCLA researchers are using retrocyclins-1 and 2 as platforms to develop analogs with improved pharmacotherapeutic properties.
- Supplementary Information
- Patent Number: US6713078B2
Application Number: US2002141645A
Inventor: Lehrer, Robert I. | Waring, Alan J. | Cole, Alexander M. | Hong, Teresa B.
Priority Date: 18 Apr 2001
Priority Number: US6713078B2
Application Date: 6 May 2002
Publication Date: 30 Mar 2004
IPC Current: C07K000764 | A61K003800
US Class: 424405 | 5140023 | 5140029 | 5140037 | 530300 | 530317 | 530326 | 530328 | 514002 | 514009 | 514015
Assignee Applicant: The Regents of the University of California
Title: Retrocyclins: antiviral and antimicrobial peptides
Usefulness: Retrocyclins: antiviral and antimicrobial peptides
Summary: The peptides and methods are useful for preventing retroviral infections in cells susceptible to bacterial or viral infections, or treating patients having the infections (claimed), such as HIV (human immunodeficiency virus), sexually transmitted diseases, bacterial vaginosis, or ophthalmic infections. This retrocyclin-mediated killing is useful for modeling and screening novel antibiotics.
Novelty: New isolated retrocyclin peptide, useful for preventing retroviral infections in cells susceptible to bacterial or viral infections or treating patients having the infections, such as HIV, sexually transmitted diseases, vaginosis
- Industry
- Disease Diagnostic/Treatment
- Sub Category
- Other Disease
- Application No.
- 6713078
- Others
-
State of Development
Retrocyclins and other theta-defensins have been synthesized and shown to protect various CD4+ human cells from infection by HIV-1 in vitro. Our current lead compound, retrocyclin-2, shows strong activity against laboratory-adapted strains of HIV-1, including IIIB (T cell tropic) and JR-CSF (M-tropic). It is also active against primary HIV-1 isolates representing subtypes A, B, C, CRF01, D, G, and various recombinant subtypes. Its efficacy is not restricted by co-receptor (e.g., R5, X4 and R5X4) specificity.The mechanism of action of retrocyclins has been studied. Their effectiveness against HIV-1 results from the prevention of viral entry, and is correlated to their ability to bind CD4 and gp120 with high affinity. Surface plasmon resonance experiments revealed that retrocyclin-2s affinity (Kd) for gp120 was 9.4 nM and that its affinity for CD4 was 6.7 nM. Fluorescence confocal microscopy of T cells treated with fluorescent RC-101 (an active analogue of retrocyclin-1) revealed surface patches wherein retrocyclin and CD4 were co-localized, without evident peptide internalization. Additional information relevant to the activities and antiviral mechanisms of retrocyclins exists, and can be provided to interested parties after appropriate confidentiality agreements are established.
Background
Defensins are cysteine-rich, cationic antimicrobial peptides expressed by leukocytes and epithelial cells of mammals and birds. These peptides, which can be considered endogenous antibiotics, play an important role in innate host defense against pathogens due to their antibacterial, antifungal and antiviral activities. Three defensin subfamilies exist in vertebrates: alpha-defensins, beta-defensins, and theta (circular) minidefensins. All of these have largely beta-sheet structures that are stabilized by three intramolecular cystine disulfide bonds, and derive from a common ancestral gene. Theta defensins are much smaller (18 amino acid residues) than alpha or beta defensins (29-45 residues), and their antiviral properties are considerably more robust than their antibacterial and antifungal effects.
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Retrocyclin: A novel Primate Peptide that Protects Cells from Infection by T-and M-Tropic Strains of HIV-1
Circular Minidefensins and Posttranslational Generation of Molecular Diversity
Homodimeric Theta-Defensins from Rhesus Macaque Leukocytes: Isolation, Synthesis, Antimicrobial Activities and Bacterial Binding Properties of the Cyclic Peptides
Three-dimensional structure of RTD-1, a cyclic antimicrobial defensin from Rhesus macaque leukocytes.Additional Technologies by these Inventors
Tech ID/UC Case
20540/2001-329-0
Related Cases
2001-329-0
- *Abstract
-
None
- *IP Issue Date
- Mar 30, 2004
- *Principal Investigator
-
Name: Lee Ming Boo
Department:
Name: Alexander Cole
Department:
Name: Teresa Hong
Department:
Name: Robert Lehrer
Department:
Name: Tung Nguyen
Department:
Name: Alan Waring
Department:
Name: Otto Yang
Department:
Name: Chengquan Zhao
Department:
- Country/Region
- USA
