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chemically-related P 1-P 1' PheΨ[CH(OH)CH 2] Phe-modified lead has been reported [63] to yield
effective peptidomimetic inhibitors of the HIV-1 protease (56; Figure 12). The pyrrolidinone-type lead
has shown enhanced cellular permeability relative to its peptide backbone-type counterparts. In a third
approach guided by HIV substrate-based design, the cleavage site dipeptide Phe-Pro was substituted by
the “transition state” bioisostere to provide the highly potent and selective HIV protease inhibitor 57, a
P 1-P 1' PheΨ[CH(OH)CH 2N] Pro-modified heptapeptide [64]. As compared to this pseudopeptide, a
pioneering effort focused on peptide ligand structure-based design provided a second series of highly
potent, selective, and cellularly-active HIV protease inhibitors [50] as represented by the recently FDAapproved
anti-HIV drug 44 (Saquinavir). The design of still more HIV protease inhibitors having novel
chemical structures (e.g., C 2-symmetric scaffolding, P 1-P 1' “transition state” bioisostere cyclization, and
achiral nonpeptide template replacement) has progressed at an extraordinary pace (for reviews see
Reference 65), and in a majority of cases such work has been strongly impacted by knowledge of the 3D
structure of the target enzyme and/or inhibitor complexes of it (see below).
A second example of protease inhibitor design that properly illustrates the peptide scaffold-based
approach is that of thrombin inhibitors. Work with these compounds led to the identification of highly
potent, selective, and in vivo-effective lead compounds. A member of the serine protease family,
thrombin cleaves a number of substrates (e.g., fibrinogen) and activates its platelet receptor (a G-proteincoupled
receptor) by proteolysis of the extracellular N-terminal domain which results in self-activation
(for a review see Reference 66). Initial lead inhibitors of thrombin were substrate-based, including the
fibrinogen P 3-P 1 Phe-Pro-Arg sequence [67] and simple Arg derivatives such as Tos-Arg-OMe [68].
Also, the natural product cyclothreonide-A, a macrocyclic peptide containing a Pro-Arg ketoamide
sequence, provided an inhibitory peptide ligand lead [69]. As shown collectively in Figure 13,
compounds 52 and 58–60 provided the opportunity to try different strategies to advance the design of
thrombin inhibitors. Particularly noteworthy from these early peptidomimetic lead discovery studies was
the design effort [70] that led to the highly potent thrombin inhibitor 52 (Agatroban), a sulfonamidemodified
Arg derivative, which incorporated an unusual cyclic amino acid substituent C-terminal to the
P 1 moiety as opposed to reactive electrophilic groups (e.g., ketone, aldehyde, or boronic acid).
Interestingly, replacement of the Arg side chain moiety within a structurally similar analog 60 by a
amidinobenzyl group was shown [71] to be optimal when the stereochemistry at the P 1 α-carbon has a Dconfiguration
suggesting that the mode of binding may be different for 52 versus 60. In this regard, xray
crystallographic analysis of thrombin-inhibitor complexes (see below) have provided insight in the
interpretation of the structure-activity relationships of the aforementioned lead compounds.
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