# SYNTHESIS AND ACTIVITY OF CYCLOSPORIN ANALOGUES

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 1992 · $212,096

## Abstract

Cyclosporine A (Sandimmune) (CSA) is a cyclic undecapeptide containing the
novel amino acid, 2S-N-methyl-3R-hydroxy-4R-methyl-6E-octenoic acid,
abbreviated MeBmt.  Cyclosporine A constitutes a basic innovation in
immunology and related fields, with potential applications for treatment of
long term chronic autoimmunity diseases if less-toxic analogs can be
found.  The objective of this competitive renewal is to continue the
chemical synthesis of novel CSA analogs and to develop the chemistry
necessary for their synthesis.  The work will begin by extending our
discovery of the BOP-C1 coupling method for coupling N-methyl amino acids
together in solution to the stepwise synthesis of CSA both in solution and
on solid phase resins.  Our new methods for synthesizing optically active
2N-methyl-3-hydroxy amino acids will be extended to the synthesis of
2S-N-methyl-3R-hydroxy-4R-methyl-6E-octenoic acid, and to analogs of this
amino acid.  These novel amino acids will be incorporated into the
1-position of CSA.  Our successful synthesis of CSA will be modified to
permit the design and synthesis of conformationally constrained analogs of
CSA that will permit us to determine conformational features of the
bioactive conformation of CSA needed for selective binding at its
receptors.  Three types of analogs will be synthesized:  bicyclic
disulfides; dipeptidyl lactams and bicyclic N-alkylsubstituents.  The
appropriate control peptides containing standard amino acids will be
synthesized as standards.  The synthetic analogs will be assayed for
inhibition of ConA stimulated thymocytes, for inhibition of antigen drive
proliferation, and for binding to calmodulin and cyclophilin.  A major
emphasis will be to try to determine if selectivity for individual
receptors is possible as this will point the way to the synthesis of less
toxic analogs useful in the treatment of chronic autoimmune diseases.  The
design of the analogs will be carried out using the SYBYL molecular
graphics software on our Evans Sutherland PS-300.  NMR data will be
obtained at 500 MHz to establish product structure and conformational
similarity to CSA.

## Key facts

- **NIH application ID:** 3156165
- **Project number:** 5R01AR032007-10
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **SAM.gov UEI:** LCLSJAGTNZQ7
- **Principal Investigator:** DANIEL H RICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $212,096
- **Award type:** 5
- **Project period:** 1983-03-01 → 1995-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3156165

## Citation

> US National Institutes of Health, RePORTER application 3156165, SYNTHESIS AND ACTIVITY OF CYCLOSPORIN ANALOGUES (5R01AR032007-10). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3156165. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*